2-oxo-1-pyrrolidine derivatives

ABSTRACT

The present invention concerns 2-oxo-1-pyrrolidine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.

INTRODUCTION

The present invention concerns 2-oxo-1-pyrrolidine derivatives,processes for preparing them, pharmaceutical compositions containingthem and their use as pharmaceuticals.

European Patent No. 0 162 036 B1 discloses compound(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, which is known under theInternational Nonproprietary Name (INN) Levetiracetam.

Levetiracetam, a laevorotary compound, is disclosed as a protectiveagent for the treatment and prevention of hypoxic and ischemic typeaggressions of the central nervous system. This compound is alsoeffective in the treatment of epilepsy, a therapeutic indication forwhich it has been demonstrated that its dextrorotatory enantiomer(R)-α-ethyl-2-oxo-1-pyrrolidine acetamide, also known from EuropeanPatent No. 0 165 919 B1, completely lacks activity (Gower A. J. et al.,Eur. J. Pharmacol. (1992), 222, 193-203).

Belavin I. Yu. et al. (Khimiko-Farmatsevticheskii Zhurnal (1992), 26(9-10), 74-76) discloses1-[1-(1H-benzimidazol-1-yl)ethyl]-2-pyrrolidinone and its anticonvulsantactivity.

EP 172 096 discloses 3-imidazol-[1,2-a]pyridine derivatives fortherapeutic applications.

U.S. Pat. No. 6,303,638 discloses 3-pyridine derivatives for treatmentof CNS disorders responsive to the administration of a m-nAChRmodulator.

EP 1 020 447 discloses 1H-pyrazol-5-yl derivatives as plant diseasecontrol agents.

It has now surprisingly been found that certain 2-oxo-1-pyrrolidinederivatives demonstrate markedly improved therapeutic properties.

U.S. Pat. No. 5,334,720 discloses 4-diphenylpyrrolidineones for thetreatment of epilepsy.

WO 2005/054188 discloses imidazole derivatives having the formula A

The imidazole or benzimidazole is attached by a nitrogen to themethylene linker of the pyrrolidinone.

SUMMARY OF THE INVENTION

The invention provides compounds having the formula (I) theirgeometrical isomers, enantiomers, diastereoisomers and mixtures, or apharmaceutically acceptable salt thereof,

in particular for the manufacture of a medicament for the treatment orprevention of epilepsy, epileptogenesis, seizure disorders, convulsions,Parkinson's disease, dyskinesia induced by dopamine replacement therapy,tardive dyskinesia induced by administration of neuroleptic drugs,Huntington Chorea, and other neurological disorders including bipolardisorders, mania, depression, anxiety, attention deficit hyperactivitydisorder (ADHD), migraine, trigeminal and other neuralgia, chronic pain,neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia,cocaine abuse, stroke, myoclonus, tremor, essential tremor, simple orcomplex tics, Tourette syndrome, restless leg syndrome and othermovement disorders, neonatal cerebral haemorrhage, amyotrophic lateralsclerosis, spasticity and degenerative diseases, bronchial asthma,asthmatic status and allergic bronchitis, asthmatic syndrome, bronchialhyperreactivity and bronchospastic syndromes as well as allergic andvasomotor rhinitis and rhinoconjunctivitis.

Further aspects of the invention will become apparent from the detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds having the formula I as wellas their geometrical isomers, enantiomers, diastereoisomers andmixtures, or a pharmaceutically acceptable salt thereof,

whereinR¹ is hydrogen, C₁₋₁₂ alkyl, aryl or heterocycle;R² is hydrogen; or R¹ and R² are linked together to form a C₃₋₆cycloalkyl;R³ is either

-   a) an unsubstituted or substituted heterocycle linked to the rest of    the molecule via one of its C atoms; or-   b) an unsubstituted or substituted heterocycle linked to the rest of    the molecule via one of its N atoms selected from the group    consisting of-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-1,2,3-triazol-1-yl;-   1H-pyrrol-1-yl;-   1H-tetrazol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.    R⁴ is hydrogen; C₁₋₁₂ alkyl optionally substituted by halogen, C₁₋₄    alkoxy, C₁₋₄ alkylthio, azido, nitrooxy or aryl; C₂₋₁₂ alkenyl;    C₂₋₁₂ alkynyl; aryl non-substituted by a cycloalkoxy; azido;    alkoxy-carbonylamino; arylsulfonyloxy; or heterocycle;    R⁵ is hydrogen;    or R⁴ can form together with R⁵ and the 2-oxo-1-pyrrolidine ring the    following 1,3-dihydro-2H-indol-2-one cycle such as

can represent a group of formula

the asterisk * indicates the point of attachment of the substituents;R⁶ is hydrogen or halogen;R⁷ is hydrogen; nitro; halogen; heterocycle; amino; aryl; C₁₋₁₂ alkyloptionally substituted by at least one halogen; or C₁₋₁₂ alkoxyoptionally substituted by at least one halogen;R⁸ is hydrogen, C₁₋₁₂ alkyl or halogen;R⁹ is hydrogen, C₁₋₁₂ alkyl or halogen;

Not comprised by formula (I) are those molecules wherein

R⁴ is not hydrogen when R¹, R² and R⁵ are hydrogen, and R³ issubstituted or unsubstituted 3-pyridinyl; unsubstituted 4-pyridinyl;2-(phenylamino)pyrimidin-4-yl; 2-trifluoropyrimidin-4-yl; isoxazol-5-yl3-substituted by an aryl or an heterocycle; a substituted1H-pyrazol-5-yl; a substituted 1H-pyrazol-3-yl; a 3-substituted1,2,4-oxadiazol-5-yl; an unsubstituted or 1-substituted 1H-indol-3-yl;2-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]thiazol-5-yl;(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl);5-(4-methoxyphenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl;substituted or unsubstituted 1,2,4-triazol-3-yl; substituted orunsubstituted 1,2,4-triazol-5-yl;4,5,6,7-tetrahydro-2,1-benzisoxazol-3-yl; substituted4,5-dihydroisoxazol-5-yl; substituted or unsubstituted1H-1,2,3-benzotriazol-3-yl; 5-substituted 1,2,4-oxadiazol-3-yl;unsubstituted 1H-imidazo[4,5-c]pyridin-2-yl;1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-purin-9-yl; substituted orunsubstituted 2-thienyl; substituted or unsubstituted 2-furyl;substituted or unsubstituted 2-pyrrolyl; substituted to unsubstituted2-benzimidazol-2-yl; or 1-substituted 1H-indol-2-yl;R⁴ is not phenyl when R¹, R² and R⁵ are hydrogen, and R³ is asubstituted 1,2,4-triazol-3-yl; a substituted 1,2,4-triazol-5-yl; orunsubstituted 1H-benzimidazol-2-yl;R⁴ is not hydrogen or phenyl when R¹ is hydrogen or C₁₋₁₂ alkyl, R² andR⁵ are hydrogen, and R³ is a substituted or unsubstituted non aromaticheterocycle;R⁴ is not hydrogen when R¹ is C₁₋₁₂ alkyl, R² and R⁵ are hydrogen, andR³ is a 3-substituted 1,2,4-oxadiazol-5-yl or unsubstituted 3-indolyl;R⁴ is not hydrogen when R¹ is phenyl, C₁₋₁₂ alkyl or heterocycle, R² andR⁵ are hydrogen, and R³ is unsubstituted 1,2,3-benzotriazol-1-yl orunsubstituted 1,2,4-triazol-1-yl;R¹ is not 1-pyrrolidin-2-one when R², R⁴ and R⁵ are hydrogen, and R³ is2-furyl; and R¹ is not 4-(2-pyrimidinyl)-1-piperazinyl when R², R⁴ andR⁵ are hydrogen, and R³ is 1-methyl-1H-pyrrol-2-yl.

In a specific embodiment, R³ is a substituted or unsubstitutedunsaturated heterocycle comprising at least one sp² hybridized nitrogenin the beta-, gamma- or delta-position of the carbon attached to themethylpyrrolidinone moiety; or a substituted or unsubstitutedheterocycle linked to the rest of the molecule via one of its N atomsselected from the group consisting of 1H-1,2,3-benzotriazol-1-yl;1H-imidazo[4,5-b]pyridin-1-yl; 3H-imidazo[4,5-b]pyridin-3-yl;7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl;2,3-dihydro-1H-indol-1-yl; 9H-purin-9-yl;1H-pyrazolo[3,4-b]pyridin-1-yl; 2H-pyrazolo[3,4-b]pyridin-2-yl;1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl;3,4-dihydroquinolin-1(2H)-yl; 8H-isothiazolo[5,4-b]indol-8-yl;1H-1,2,4-triazol-1-yl; 1H-1,2,3-triazol-1-yl; 1H-pyrrol-1-yl;1H-tetrazol-1-yl;

2-chloro-1H-benzimidazol-1-yl.

In a further specific embodiment, R³ is a substituted or unsubstitutedaromatic heterocycle comprising at least one sp² hybridized nitrogen inthe beta-, gamma- or delta-position of the carbon attached to themethylpyrrolidinone moiety; or a substituted or unsubstitutedheterocycle linked to the rest of the molecule via one of its N atomsselected from the group consisting of 1H-1,2,3-benzotriazol-1-yl;1H-imidazo[4,5-b]pyridin-1-yl; 3H-imidazo[4,5-b]pyridin-3-yl;7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl;2,3-dihydro-1H-indol-1-yl; 9H-purin-9-yl;1H-pyrazolo[3,4-b]pyridin-1-yl; 2H-pyrazolo[3,4-b]pyridin-2-yl;1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl;3,4-dihydroquinolin-1(2H)-yl; 8H-isothiazolo[5,4-b]indol-8-yl;1H-1,2,4-triazol-1-yl; 1H-pyrrol-1-yl; 2-chloro-1H-benzimidazol-1-yl.

More specifically, the compounds of the present invention are thosecovered by formula (I), their diastereomers and mixtures, or apharmaceutically acceptable salt thereof.

R¹ is hydrogen, substituted or unsubstituted C₁₋₁₂ alkyl, substituted orunsubstituted aryl or substituted or unsubstituted 3-8 memberedheterocycle.R² is hydrogen. Alternatively, R¹ and R² may be linked together in sucha way to form a C₃₋₆ cycloalkyl.R³ is either

-   -   (a) a substituted or unsubstituted heterocycle linked to the        rest of the molecule via one of its C atoms, said heterocycle is        selected from the group consisting of:

-   1H-benzimidazol-6-yl;

-   1H-benzimidazol-7-yl;

-   imidazo[1,2-a]pyridin-3-yl;

-   imidazo[1,2-a]pyrimidin-3-yl;

-   imidazo[1,2-b][1,2,4]triazin-7-yl;

-   imidazo[1,2-b]pyridazin-3-yl;

-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;

-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

-   imidazo[2,1-b][1,3]thiazol-5-yl;

-   3H-imidazo[4,5-b]pyridin-7-yl;

-   1H-imidazol-4-yl;

-   1H-imidazol-5-yl;

-   1H-indol-2-yl;

-   1H-indol-3-yl;

-   1H-indol-4-yl;

-   1H-indol-7-yl;

-   isoxazol-4-yl;

-   1H-pyrazol-4-yl;

-   1H-pyrazol-5-yl;

-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;

-   1H-pyrazolo[3,4-b]pyridin-3-yl;

-   pyridazin-4-yl;

-   pyridin-2-yl;

-   pyridin-3-yl;

-   pyridin-4-yl;

-   1H-pyrrolo[2,3-b]pyridin-3-yl;

-   1H-pyrrolo[2,3-b]pyridin-4-yl;

-   1H-pyrrolo[2,3-b]pyridin-5-yl;

-   1H-pyrrolo[2,3-c]pyridin-2-yl;

-   1H-pyrrolo[2,3-c]pyridin-3-yl;

-   1H-pyrrolo[3,2-b]pyridin-3-yl;

-   1H-pyrrolo[3,2-c]pyridin-2-yl;

-   1H-pyrrolo[3,2-c]pyridin-3-yl;

-   1,3,4-thiadiazol-2-yl;

-   1,3-thiazol-5-yl;

-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;

-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;

-   indolizin-3-yl;

or R³ is

-   (b) a substituted or unsubstituted heterocycle linked to the rest of    the molecule via one of its N atoms, said heterocycle is selected    from the group consisting of:-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.    R⁴ in formula (I) is selected from the group comprising or    consisting of hydrogen; C₁₋₁₂ alkyl optionally substituted by    halogen, C₁₋₄ alkoxy, C₁₋₄ alkylthio, azido, nitrooxy or an aryl;    C₂₋₁₂ alkenyl optionally substituted by halogen; C₂₋₁₂ alkynyl    optionally substituted by halogen; azido; alkoxycarbonylamino;    arylsulfonyloxy; a substituted or unsubstituted aryl; or a 3-8    membered substituted or unsubstituted heterocycle;

In a specific embodiment R⁴ is hydrogen; or R⁴ is C₁₋₁₂ alkyl or a C₁₋₆alkyl, optionally substituted by halogen, C₁₋₄ alkoxy, C₁₋₄ alkylthio,azido or nitrooxy; or R⁴ is C₂₋₁₂ alkenyl or a C₁₋₆ alkenyl optionallysubstituted by halogen; or R⁴ is C₂₋₁₂ alkynyl or a C₁₋₆ alkynyloptionally substituted by halogen; or R⁴ is alkoxycarbonylamino.

R⁵ is hydrogen;

Alternatively R⁴ may form together with R⁵ and the 2-oxo-1-pyrrolidinering a 1,3-dihydro-2H-indol-2-one ring of the following structure:

The asterisk * indicates the point of attachment of the substituents;R⁶ is hydrogen or halogen.R⁷ in formula (I) is selected from the group comprising or consisting ofhydrogen; nitro; halogen; heterocycle; amino; aryl; C₁₋₁₂ alkyloptionally substituted by at least one halogen; or C₁₋₁₂ alkoxyoptionally substituted by at least one halogen.R⁸ in formula (I) is selected from the group comprising or consisting ofhydrogen, C₁₋₁₂ alkyl optionally substituted by halogen, or halogen.R⁹ in formula (I) is selected from the group comprising or consisting ofhydrogen, C₁₋₁₂ alkyl optionally substituted by halogen, or halogen.

A further aspect of the present invention consists in compounds offormula (I) wherein

R¹ and R² are both hydrogen.

R³ is:

-   (a) a substituted or unsubstituted heterocycle linked to the rest of    the molecule via one of its C atoms selected from the group    consisting of:-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl.

Alternatively R³ is:

-   (b) a substituted or unsubstituted heterocycle linked to the rest of    the molecule via one of its N atoms selected from the group    consisting of:-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

R⁴ in formula (I) is selected from the group comprising or consisting ofhydrogen; C₁₋₁₂ alkyl optionally substituted by halogen or C₁₋₄ alkoxy;C₂₋₁₂ alkenyl optionally substituted by halogen; C₂₋₁₂ alkynyloptionally substituted by halogen.

In a further specific embodiment R⁴ is n-propyl, 2,2,2-trifluoroethyl,2-chloro-2,2-difluoroethyl, 2 bromo-2,2-difluoroethyl,2,2-difluorovinyl.

In another specific embodiment R⁴ is phenyl, 2,3,5-trifluorophenyl or3-chloro-4-fluorophenyl.

R⁵ is hydrogen;

A further embodiment of the present invention consists in compounds offormula (I) wherein R⁴ forms together with R⁵a1,3-dihydro-2H-indol-2-one ring

The asterisk * indicates the point of attachment of the heteroarylalkylene substituent, and whereinR⁶ is hydrogen;R⁷ is chlorine;R⁸ is hydrogen;R⁹ is hydrogen.

A further embodiment of the present invention consists in compounds offormula (I) wherein R³ is a substituted or unsubstituted heterocyclelinked to the rest of the molecule via one of its C atoms and isselected from the group consisting of:

-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl.

In a further specific embodiment R³ is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of:

-   imidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-pyrazol-4-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1,3-thiazol-5-yl;    Said heterocycles are optionally substituted by e.g. a methyl,    n-propyl, trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine,    iodine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,    cyclopropylmethoxy, cyclobutylmethoxy, amino, methylamino,    cyclopropylamino, cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl,    benzyl or 3-thienyl.

In a further specific embodiment R³ is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of: 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl,6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl,6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl,6-chloroimidazo[2,1-b][1,3]thiazol-5-yl,2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl, 5-chloro-1H-imidazol-4-yl,5-bromo-1H-imidazol-4-yl, 4-bromo-1H-imidazol-5-yl,4-chloro-1H-imidazol-5-yl, 1H-imidazol-5-yl, 1-methyl-1H-imidazol-5-yl,4-chloro-1-methyl-1H-imidazol-5-yl, 1H-pyrazol-4-yl,1H-pyrrolo[2,3-b]pyridin-3-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R³ is a heterocycle linked to the rest of themolecule via one of its C atoms and is a substituted or unsubstitutedimidazo[1,2-a]pyridin-3-yl.

Said imidazo[1,2-a]pyridin-3-yl is optionally substituted by e.g. amethyl, cyclopropyl, bromine, chlorine, fluorine, iodine.

In a further specific embodiment R³ is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of: imidazo[1,2-a]pyridin-3-yl,6-methylimidazo[1,2-a]pyridin-3-yl, 2-chloroimidazo[1,2-a]pyridin-3-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R³ is a substituted or unsubstituted heterocyclelinked to the rest of the molecule via one of its N atoms and isselected from the group consisting of:

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H-indol-1-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

A specific further embodiment of the present invention consists incompounds of formula (I) wherein R³ is a heterocycle linked to the restof the molecule via one of its N atoms and is selected from the groupconsisting of:

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl;    Said heterocycles may optionally be substituted by trifluoromethyl,    cyclopropyl, bromine, chlorine, fluorine, methoxy or cyano.

In a further specific embodiment R³ is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of 6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl,6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl,1H-pyrrolo[3,2-b]pyridin-1-yl, 2,5-dichloro-1H-pyrrol-1-yl,2-chloro-5-methoxy-1H-benzimidazol-1-yl,5-bromo-2-chloro-1H-benzimidazol-1-yl or2,5-dichloro-1H-benzimidazol-1-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R¹, R² and R⁵ are hydrogen.

R⁴ is a C₁₋₆ alkyl optionally substituted by halogen, a C₂₋₆ alkenyloptionally substituted by halogen or C₂₋₁₂ alkynyl optionallysubstituted by halogen.

R³ is selected from the group consisting of;

-   imidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-pyrazol-4-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1,3-thiazol-5-yl;    and optionally substituted by methyl, n-propyl, trifluoromethyl,    cyclopropyl, bromine, chlorine, fluorine, iodine, methoxy, ethoxy,    propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy,    cyclobutylmethoxy, amino, methylamino, cyclopropylamino,    cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl, benzyl or 3-thienyl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R¹, R² and R⁵ are hydrogen.

R⁴ is a C₁₋₆ alkyl optionally substituted by halogen, a C₂₋₆ alkenyloptionally substituted by halogen or C₂₋₁₂ alkynyl optionallysubstituted by halogen.

R³ is selected from the group consisting of

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl;    optionally substituted by trifluoromethyl, cyclopropyl, bromine,    chlorine, fluorine, methoxy or cyano.

A further embodiment of the invention consists in compounds of formula(I), their diastereomers and mixtures, or a pharmaceutically acceptablesalt thereof.

R¹, R² and R⁵ are hydrogen.R³ is a substituted or unsubstituted heterocycle linked to the rest ofthe molecule via one of its C atoms, said heterocycle is selected fromthe group consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl;

Particularly preferred are imidazo[1,2-a]pyridin-3-yl;imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b]pyridazin-3-yl;1H-imidazol-4-yl; 1H-imidazol-5-yl;

R⁴ is a substituted or unsubstituted phenyl moiety;

A further embodiment of the present invention consists in compounds offormula (I) wherein R¹ is hydrogen or C₁₋₁₂ alkyl;

R² is hydrogen;R³ is an aromatic 5-membered heterocycle linked to the rest of themolecule via one of its C atoms;R⁴ is hydrogen, C₁₋₁₂ alkyl or aryl;R⁵ is hydrogen;Alternatively, R⁴ can form together with R⁵ and the 2-oxo-1-pyrrolidinering the following 1,3-dihydro-2H-indol-2-one cycle

wherein the asterisk * indicates the point of attachment of thesubstituents;R⁶ is hydrogen or halogen;

In this embodiment R⁴ may not be hydrogen when R³ is substituted1H-pyrazol-5-yl. Also this embodiment does not comprise5-(2′-oxo-1′-pyrrolidinyl)methyl-1,3,4-tricarbomethoxy-pyrazole which isdisclosed in A. Padwa et al J. Org. Chem. 2000, 65, 5223-5232 withoutany biological activity though.

In this embodiment wherein R³ is an aromatic 5-membered heterocyclelinked to the rest of the molecule via one of its C atoms, specificmoieties R³ may be selected from 1,3-thiazol-5-yl, 1H-imidazol-4-yl,1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,2-oxo-2,3-dihydro-1,3-thiazol-5-yl, each of them being optionallysubstituted by 1 to 3 substituents independently selected from methyl,chlorine, bromine, amino, methylamino, dimethylamino,(2-oxo-4-propyl-pyrrolidin-1-yl)methyl, 1-pyrrolidinyl, amido, cyano,methoxy, phenyl, 4-methylphenyl-sulfonyl, benzyl or2-(benzylamino)-2-oxoethyl.

In this embodiment, more specific moieties R³ are selected from2-(methylamino)-1,3-thiazol-5-yl; 2-pyrrolidin-1-yl-1,3-thiazol-5-yl;5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl;1-methyl-1H-imidazol-5-yl; 4-bromo-1-methyl-1H-imidazol-5-yl;4-chloro-1H-imidazol-5-yl; 4-chloro-1-methyl-1H-imidazol-5-yl;4-cyano-1-methyl-1H-imidazol-5-yl; 1H-pyrazol-4-yl;3,5-dimethyl-1H-pyrazol-4-yl; 3-methyl-1H-pyrazol-4-yl.

In this embodiment, most specific moieties R³ are selected from5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl;4-bromo-1-methyl-1H-imidazol-5-yl; 4-chloro-1-methyl-1H-imidazol-5-yl;1H-pyrazol-4-yl.

Still in this embodiment, a specific moiety R¹ is selected from hydrogenor ethyl.

Still in this embodiment, a specific moiety R⁴ is selected fromhydrogen, n-propyl, 2,3,5-trifluorophenyl or phenyl.

A further embodiment of the present invention consists in compoundshaving the specific formula (Ia).

In formula (Ia) the substituent R¹⁰ is hydrogen; halogen; C₁₋₄ alkyloptionally substituted by at least one halogen; C₁₋₄ alkoxy;methoxycarbonyl; nitro; amino; alkylamino; amido; or alkanoyl-amino.Preferably R¹⁰ is hydrogen.

R¹¹ is hydrogen; halogen; C₁₋₄ alkyl optionally substituted by at leastone halogen; C₁₋₄ alkoxy; methoxycarbonyl; nitro; amino; alkylamino;amido; or alkanoylamino. Preferably R¹¹ is hydrogen.

R⁴ is C₁₋₄ alkyl optionally substituted by at least one halogen; or C₂₋₄alkenyl optionally substituted by at least one halogen. Preferably R⁴ isn-propyl.

Still in this aspect of the invention a specific embodiment relates toan embodiment wherein R¹⁰ is selected from hydrogen; methyl; fluorine;chlorine; bromine; methoxy; methoxycarbonyl; nitro; or trifluoromethyl,while R¹¹ is selected from hydrogen; methyl; fluorine; chlorine;bromine; methoxy; methoxycarbonyl; nitro; or trifluoromethyl; and R³ isn-propyl.

Specific compounds of the present invention are those selected from thegroup consisting of:

-   1-[(1-methyl-1H-benzimidazol-6-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(1H-benzimidazol-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(8-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-iodoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(7-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6,8-dibromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6,8-dichloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propyl    pyrrolidin-2-one;-   1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-phenylimidazo[1,2-b][1,2,4]triazin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-phenylpyrrolidin-2-one;-   5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one;-   1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(benzyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(dimethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-chloro-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(methylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(ethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[6-pyrrolidin-1-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(cyclopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-(isopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2-fluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2,2-difluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2,2,2-trifluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[2-cyclopropyl-6-(cyclopropylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(3-chloro-4-fluorophenyl)pyrrolidin-2-one;-   1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclobutylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(2-cyclopropyl-6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-ethoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(cyclopropylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclobutylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carbonitrile;-   4-(2,2-difluorovinyl)-1-{[6-thien-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-pyridin-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-[(6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methylimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-phenylpyrrolidin-2-one;-   4-phenyl-1-[(5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;-   1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;-   1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[1-(1H-imidazol-4-yl)propyl]pyrrolidin-2-one;-   1-[(5-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-[(2-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-4-yl}methyl)-4-propylpyrrolidin-2-one;-   1-[(5-chloro-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-imidazol-4-yl)methyl]-5-chloro-1,3-dihydro-2H-indol-2-one;-   1-(1H-imidazol-5-ylmethyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;-   1-methyl-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;-   1-(1H-imidazol-5-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide;-   N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile;-   1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;-   1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;    benzyl    1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-2-ylcarbamate;-   1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   5-chloro-1-(1H-imidazol-5-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   1-[(2,4-dichloro-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   5-chloro-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-indol-2-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-indol-3-ylmethyl)-4-propylpyrrolidin-2-one;-   3-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-5-carbonitrile;-   1-[(2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(7-methoxy-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(trifluoromethyl)-1H-indol-3-yl]methyl}pyrrolidin-2-one;-   1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(7-fluoro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloro-2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[1H-indol-3-yl(phenyl)methyl]-4-propylpyrrolidin-2-one;-   1-[1-(1H-indol-3-yl)propyl]-4-propylpyrrolidin-2-one;-   1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   3-[(2-oxo-4-propylpyrrolidin-1-yl)(phenyl)methyl]-1H-indole-5-carbonitrile;-   1-(1H-indol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-indol-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(1-phenyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   4-(2,3,5-trifluorophenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one;-   1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-chloro-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(3-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;-   (−)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   (+)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   5-chloro-1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-1,3-dihydro-2H-indol-2-one;-   1-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(5-amino-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-5-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-methyl-6-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-methyl-6-(1H-pyrrol-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-({6-[(1E)-hex-1-enyl]-2-methylpyrazolo[1,5-a]pyrimidin-3-yl}methyl)-4-propylpyrrolidin-2-one;-   1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-hydroxy-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-propyl-1-(pyridin-3-ylmethyl)pyrrolidin-2-one;

(−)-1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one;

-   5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one;-   1-[(2-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-[(2-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one;-   1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one;-   1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one;-   1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2-pyrrolidin-1-yl-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1,3-thiazol-2(3H)-one;-   4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one;-   4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;-   4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one;-   1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-{[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}-4-phenylpyrrolidin-2-one;-   1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(3-chloro-7H-imidazo[4,5-c]pyridazin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-fluoro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(2,3-dihydro-1H-indol-1-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-2-carbonitrile;-   1-[(2-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,5-dichloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(9H-purin-9-ylmethyl)pyrrolidin-2-one;-   1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(benzylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(propylamino)-9H-purin-9-yl]methyl}pyrrolidin-2-one;-   1-({6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}methyl)-4-propylpyrrolidin-2-one;-   4-propyl-1-[(6-pyrrolidin-1-yl-9H-purin-9-yl)methyl]pyrrolidin-2-one;-   1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)pyrrolidin-2-one;-   1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(8H-isothiazolo[5,4-b]indol-8-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one;-   1-[(2,5-dichloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;-   2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;-   2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-6-carbonitrile;-   4-propyl-1-[(2,5,6-trichloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;-   1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,6-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,5-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;-   1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(pyridin-4-ylmethyl)pyrrolidin-2-one, and-   1-[(2-chloro-5-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one.

The compounds of the present invention are for use as a medicament, inparticular for disorder is selected from the group consisting ofepilepsy, epileptogenesis, seizure disorders, convulsions, Parkinson'sdisease, dyskinesia induced by dopamine replacement therapy, tardivedyskinesia induced by administration of neuroleptic drugs, HuntingtonChorea, and other neurological disorders including bipolar disorders,mania, depression, anxiety, attention deficit hyperactivity disorder(ADHD), migraine, trigeminal and other neuralgia, chronic pain,neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia,cocaine abuse, stroke, myoclonus, tremor, essential tremor, simple orcomplex tics, Tourette syndrome, restless leg syndrome and othermovement disorders, neonatal cerebral haemorrhage, amyotrophic lateralsclerosis, spasticity and degenerative diseases, bronchial asthma,asthmatic status and allergic bronchitis, asthmatic syndrome, bronchialhyperreactivity and bronchospastic syndromes as well as allergic andvasomotor rhinitis and rhinoconjunctivitis.

Specific disorders are epilepsy, dyskinesia induced by dopaminereplacement therapy, chronic pain, neuropathic pain.

A further aspect of the present invention relates to a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)in combination with a pharmaceutically acceptable diluent or carrier.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“C₁₋₁₂ alkyl” or “C₁₋₆ alkyl” refers to alkyl groups having 1 to 12 or 1to 6 carbon atoms. This term is exemplified by groups such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, trifluoromethyl and the like.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl). Preferred aryl include phenyl,naphthyl, phenantrenyl and the like.

“Heterocycle” refers to a saturated or unsaturated ring systemcontaining, in addition to carbon atoms, at least one hetero atom, suchas nitrogen, oxygen and/or sulfur.

“Heterocycle” includes both “heteroaryl” and “heterocycloalkyl”.

Specific heterocycles comprise the following

wherein the asterisk * indicates the point of attachment.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl or benzoquinolyl, imidazopyrimidine, imidazopyridazine,imidazothiazole, imidazothiadiazole.

“C₂₋₆ alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (vinyl, —CH═CH₂), n-2-propenyl(allyl, —CH₂CH═CH₂) and the like.

“C₂₋₆ alkynyl” refers to alkynyl groups preferably having from 2 to 6carbon atoms and having at least 1-2 sites of alkynyl unsaturation,preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH₂C≡CH),and the like.

“C₃₋₈ cycloalkyl” refers to a saturated carbocyclic group of from 3 to 8carbon atoms having a single ring (e.g., cyclohexyl) or multiplecondensed rings (e.g., norbornyl). Preferred cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and thelike.

“Heterocycloalkyl” refers to a C₃₋₈ cycloalkyl group according to thedefinition above, in which 1 to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined ashydrogen or C₁₋₆ alkyl. Preferred heterocycloalkyl include pyrrolidine,piperidine, piperazine, 1-methylpiperazine, morpholine, and the like.

“Alkoxy” refers to the group —O—R where R includes “C₁₋₆ alkyl”, “C₂₋₆alkenyl”, “C₂₋₆ alkynyl”, “C₃₋₈ cycloalkyl”, “heterocycloalkyl”, “aryl”,“heteroaryl”.

“Amino” refers to the group —NRR′ where each R, R′ is independentlyhydrogen, “C₁₋₆ alkyl”, “C₂₋₆ alkenyl”, “C₂₋₆ alkynyl”, “C₃₋₈cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, and where R andR′, together with the nitrogen atom to which they are attached, canoptionally form a 3-8-membered heterocycloalkyl ring.

“Amido” refers to the group —C(═O)NRR′ where each R, R′ is independentlyhydrogen, “C₁₋₆ alkyl”, “C₂₋₆ alkenyl”, “C₂₋₆ alkynyl”, “C₃₋₈cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, and where R andR′, together with the nitrogen atom to which they are attached, canoptionally form a 3-8-membered heterocycloalkyl ring.

“Sulfanyl” refers to the group —SR where R is “C₁₋₆ alkyl”, “C₂₋₆alkenyl”, “C₂₋₆ alkynyl”, “C₃₋₈ cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Sulfinyl” refers to the group —S(═O)R where R is “C₁₋₆ alkyl”, “C₂₋₆alkenyl”, “C₂₋₆ alkynyl”, “C₃₋₈ cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Sulfonyl” refers to the group —S(═O)₂R where R is “C₁₋₆ alkyl”, “C₂₋₆alkenyl”, “C₂₋₆ alkynyl”, “C₃₋₈ cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups canoptionally be substituted with from 1 to 5 substituents selected fromthe group consisting of “C₁₋₆ alkyl”, “C₂₋₆ alkenyl”, “C₂₋₆ alkynyl”,“cycloalkyl”, “heterocycloalkyl”, “amino”, “aryl”, “heteroaryl”,“alkoxy”, “halogen”, cyano, hydroxy, mercapto, nitro, “amido”,“sulfanyl”, “sulfinyl”, “sulfonyl” and the like.

The “pharmaceutically acceptable salts” according to the inventioninclude therapeutically active, non-toxic acid or base salt forms whichthe compounds of formula I are able to form.

The acid addition salt form of a compound of formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula I containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.,45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

Some of the compounds of formula I may also exist in tautomeric forms.Such forms although not explicity indicated in the above formula areintended to be included within the scope of the present invention.

The invention also includes within its scope pro-drug forms of thecompounds of formula I and its various sub-scopes and sub-groups.

The compounds of formula I according to the invention can be preparedanalogously to conventional methods as understood by the person skilledin the art of synthetic organic chemistry.

A. According to one embodiment, compounds having the general formula Imay be prepared by chlorination of a compound of formula II and reactionof the corresponding derivative of formula III with an heterocycle offormula R³H, or by direct condensation of a compound of formula II withan heterocycle of formula R³H, according to the equation:

wherein R¹, R², R³, R⁴ and R⁵ have the same definitions as defined abovefor compounds of formula I.

When R³ is an heterocycle linked to the rest of the molecules via its Natom, this condensation is better performed under basic conditions usingstrong bases like LiH or NaH, in DMF, THF or the like.

The synthesis of intermediates of formula III may be carried out usingthionyl chloride (or any other chlorination agent such as HCl, POCl₃,PCl₅ . . . ) neat or in toluene at a temperature ranging from 20° C. to80° C.

The condensation of a compound of formula III with a compound of formulaR³H can be performed in 1,1′,2,2′-tetrachloroethane toluene, dioxane inthe presence of a lewis acid such as AlCl₃ at a temperature ranging from20° C. to 80° C.

The direct condensation of a compound of formula II with an heterocycleof formula R³H can be performed according to any method known to theperson skilled in the art (eg PTSA/Toluene or TFA, or use of catalyticamount of N,N-diethylcarbamoyl chloride in acetonitrile under microwaveirradiation).

Compounds of formula II may be prepared by hydroxyalkylation of acompound of formula V with a carbonyl derivative of formula IV accordingto the equation

wherein R¹, R², R⁴ and R⁵ are defined as described above for compoundsof formula I. This reaction may be carried out by heating thepyrrolidone derivative V with the aldehyde IV (or its syntheticequivalent such as paraformaldehyde in the case of formaldehyde) in thepresence of an acid or a base such as CF₃CO₂H or NaOH. Compounds offormula II may also be generated in situ using microwave technology.

B. According to another embodiment, some compounds having the generalformula I wherein R² is H, may be prepared by reductive amination of thealdehyde of formula VI with an amino acid derivative of formula VIIaccording to the equation:

wherein R¹, R³, R⁴ and R⁵ have the same definitions as described above,and R¹⁰ represents hydrogen, a C₁₋₄ alkyl group or a metal atom (such asBa²⁺ or Na⁺).

In compounds of formula VII, R⁴ can form together with R⁵ and theamino-butyrate side chain a cycle, leading to a derivative of formula(VIIa)

wherein R⁶, R⁷, R⁸, R⁹ and R¹⁰ have the same definitions as describedabove. This reaction may be carried out using the conditions describedin Abdel-Magid, A. F., Harris, B. D., Maryanoff, C. A., Synlett (1994),81-83.

The synthesis of compounds of formula VI, VII and VIIa can be done usingstandard procedure described in the literature or known by the personskilled in the art.

C. Compounds of formula I may be prepared by alkylation of a compound offormula VIII with a compound of formula V according to the equation

wherein Hal is a halogen atom, preferably Br or Cl; R¹, R², R³, R⁴ andR⁵ have the same definitions as defined above for compounds of formulaI.

This reaction may be carried out in the presence of a strong base,preferably sodium hydride, at a temperature comprised between 0 and 40°C., in an inert solvent, for example DMF, under an inert atmosphere, oras described in patent GB 1,309,692 (UCB). The synthesis of compounds offormula VIII can be done using standard procedure described in theliterature or known by the person skilled in the art.

D. Compounds of formula I may be prepared by condensation of an amine offormula IX with a halogenated acid derivative of formula X, or byreductive amination of an hydroxylactone of formula XI or XII with anamine of formula IX, according to the following equation

In compounds of formula X, X¹ represents a halogen atom, preferably aiodine or a chlorine atom, X² represents a halogen atom, preferably achlorine atom. This reaction may be carried out as described in patentapplication GB 2225322 A, or according to any method known to the personskilled in the art.

The synthesis of compounds of formula IX can be done using standardprocedure described in the literature or known by the person skilled inthe art.

E. According to another embodiment, some compounds of formula I whereinR³ is a group of formula

wherein R¹¹ is hydrogen or C₁₋₄ alkyl optionally substituted by aminogroup and the asterisk * indicates the point of attachment of the ringR³ may be prepared from the corresponding compound of formula XIII bytreatment respectively with an acidic aqueous solution or with analkylating agent as follows:

Compounds of formula XIII may be synthesized according to the methoddescribed in item B.

F. According to another embodiment, some compounds of formula I whereinR³ is 1-[2-(benzylamino)-2-oxoethyl]-1H-imidazol-5-yl may be preparedfrom compounds of formula XIII according to the equation

Basic hydrolysis and aminolysis of compounds of formula XIV areperformed according to methods known to the person skilled in the art.

Compounds of formula XIV may be prepared from the corresponding compoundof formula XIII by treatment with an alkylating agent as describedabove.

G. According to one embodiment, compounds of formula I wherein R³ is

wherein R¹³ is amino or an amino group and the asterisk * indicates thepoint of attachment of the ring R³, may be prepared by reaction of acompound of formula II with dichloroethylene, followed by reaction ofthe such obtained aldehyde derivative of formula XV with a thiourea offormula XVI as follows:

wherein R¹, R², R⁴ and R⁵ are defined as described above for compoundsof formula I. This reaction may be carried out in concentrated sulfuricacid by reacting II and a dichloroethylene at low temperature (such as0° C.).

The condensation of the aldehyde XV with a thiourea derivative XVI isperformed in an alcohol at reflux in the presence of an iodide salt(such as KI).

H. According to another embodiment, some compounds having the generalformula I may be prepared by functional group transformation.

(a) compound of formula I wherein R³ is

wherein R¹⁴ is hydrogen or C₁₋₄ alkyl optionally substituted by aminogroup, Hal is an halogen atom and the asterisk * indicates the point ofattachment of the ring R³, may be prepared from the correspondingnon-halogenated compound of formula I according to any method known tothe person skilled in the art.(b) compound of formula I wherein R³ is a 1,3-thiazol-5-yl 2-substitutedby amino or an amino group may be prepared by reaction of a compound offormula I wherein R³ is a 2-halogeno-1,3-thiazol-5-yl with respectivelyconcentrated HCl or an amine derivative according to any method known tothe person skilled in the art.(c) compound of formula I wherein R³ is a 1,3-thiazol-5-yl may beprepared by reaction of a compound of formula I wherein R³ is a2-amino-1,3-thiazol-5-yl with iso-amyl nitrite according to any methodknown to the person skilled in the art.(d) Compound of formula I bearing at least on halogen atom on to thecore heteroaryl

where R¹ are defined as described above, Hal is an halogen atom and theasterisk * indicates the point of attachment of the ring R³, may betransformed to the corresponding compound (halogen substitution byhydrogen, alkyne, alkyl, aryl, heteroaryl, amino, alkylamino, hydroxy,alkoxy, cyano, alkylthio) compound of formula I according to any methodknown to the person skilled in the art.(e) compounds bearing an alkylsulfonyl and alkyl sulfoxide moiety can beprepared from corresponding alkylthio substituted compound according toany method known to the person skilled in the art.(f) Compound of formula I

wherein R¹, R² and R³ are defined as described above may be preparedfrom compound of formula I according to any method known to the personskilled in the art.(g) compounds bearing an alkoxy substituent on position R³ can beprepared from the corresponding hydroxy derivatives according to anymethod known to the person skilled in the art.(h) compounds bearing N-oxide moiety on position R³ can be prepared fromthe corresponding aza-derivatives according to any method known to theperson skilled in the art.

In another embodiment, the present invention concerns the synthesis ofthe following intermediates:

-   methyl 3-(aminomethyl)hexanoate hydrochloride;-   6-bromo-2-methylpyrazolo[1,5-a]pyrimidine;-   6-bromo-2-(2-thienyl)pyrazolo[1,5-a]pyrimidine;-   6-bromo-2-phenylpyrazolo[1,5-a]pyrimidine;-   6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidine;-   6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidine;-   6-chloro-2-phenylpyrazolo[1,5-a]pyrimidine;-   6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde;-   2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde;-   6-bromo-2-(2-thienyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde;-   6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde;-   2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde;-   6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde;-   5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde;-   2-(2-thienyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde;-   6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde;-   ethyl 3-(aminomethyl)hexanoate hydrochloride;-   6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine;-   3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine;-   4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-one;-   2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide;-   4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   4-(2,3,5-trifluorophenyl)-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   ethyl    {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetate;-   {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetic    acid;-   4-iodo-3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole;-   3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde;-   3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde;-   1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde;-   1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-5-carbaldehyde;-   ethyl 4-amino-3-(2,3,5-trifluorophenyl)butanoate hydrochloride;-   1-({3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-({3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   ethyl 4-[(pyridazin-4-ylmethylene)amino]butanoate;-   ethyl 4-[(pyridazin-4-ylmethyl)amino]butanoate;-   5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1H-indole;-   3,3-dibromo-5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one;-   1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one;-   5-bromo-1H-pyrazolo[3,4-b]pyridine;-   2-chloro-3-(2-oxopyrrolidin-1-yl)propanal; S-ethyl    4-cyano-1-methyl-1H-imidazole-5-carbothioate;-   5-formyl-1-methyl-1H-imidazole-4-carbonitrile;-   1-(1H-imidazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   ethyl 4-{[1-(1-trityl-1H-imidazol-4-yl)propyl]amino}butanoate;-   ethyl    3-{[(2-methyl-1-trityl-1H-imidazol-5-yl)methyl]amino}propanoate;-   ethyl    3-{[(4-methyl-1-trityl-1H-imidazol-5-yl)methyl]amino}propanoate;-   1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine;-   barium bis[(2-amino-5-chlorophenyl)acetate];-   5-hydroxy-4-(2,2,2-trifluoroethyl)furan-2(5H)-one;-   1-benzyl-5-hydroxy-4-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-pyrrol-2-one;-   1-benzyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;-   4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;-   6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine;-   6-chloro-2-cyclobutylimidazo[1,2-b]pyridazine;-   2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridine;-   6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde;-   6-chloro-2-cyclobutylimidazo[1,2-b]pyridazine-3-carbaldehyde;-   2-cyclopropyl-6-fluoroimidazo[1,2-b]pyridazine-3-carbaldehyde;-   6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde;-   (6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol;-   [6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methanol;-   (6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methanol;-   (2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methanol;-   (2-cyclopropyl-6-chloroimidazo[1,2-a]pyridin-3-yl)methanol;-   6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine;-   2-(2-thienyl)pyrazolo[1,5-a]pyrimidine;-   2-(2-furyl)pyrazolo[1,5-a]pyrimidine;-   2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidine;-   2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine;-   2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidine;-   2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine;-   6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine;-   6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol;-   2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-ol;-   7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine;-   7-chloro-5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine;-   7-chloro-2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidine;-   6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine;-   5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine;-   2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidine;-   4-(2,2-difluorovinyl)-1-(hydroxymethyl)pyrrolidin-2-one;-   (6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol;-   (5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol;-   [2-(2-thienyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol;-   3-(chloromethyl)-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine;-   3-(chloromethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine;-   3-(chloromethyl)-2-(2-thienyl)pyrazolo[1,5-a]pyrimidine;-   1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridine;-   5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine;-   tert-butyl    5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate;-   tert-butyl    5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate;-   1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one;-   2,5-dichloro-1H-indole;-   1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one;-   6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine;-   (5-chloro-2-imino-1,3-thiazol-3(2H)-yl)acetic acid hydrobromide;-   methyl 3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate;-   methyl 1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate;-   methyl    3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-7-carboxylate;-   1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxylate;-   [3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol;-   [3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol;-   7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine;-   7-(chloromethyl)-3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine;-   1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-phenylpyrrolidin-2-one;-   1-{[3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   N-(4-methoxybenzyl)-2-nitroethylene-1,1-diamine;-   ethyl    2-[(4-methoxybenzyl)amino]-3-nitro-6-(trifluoromethyl)isonicotinate;-   ethyl 2-[(4-methoxybenzyl)amino]-3-nitro-6-phenylisonicotinate;-   ethyl 2-[(4-methoxybenzyl)amino]-6-methyl-3-nitroisonicotinate;-   ethyl    3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate;-   ethyl    3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridine-7-carboxylate;-   ethyl    3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridine-7-carboxylate;-   [3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol;-   [3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol;-   [3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol;-   7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;-   7-(chloromethyl)-3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridine;-   7-(chloromethyl)-3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridine;-   1-{[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   methyl 6-bromo-1H-imidazo[4,5-b]pyridine-7-carboxylate;-   methyl    6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate;-   [6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol;-   6-bromo-7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine;-   1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   [3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol;-   7-(chloromethyl)-3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridine;-   1-{[3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   [3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol;-   7-(chloromethyl)-3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridine;-   1-{[3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   3-(4-methoxybenzyl)-7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine;-   2-[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]-N,N-dimethylethylenamine;-   3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde;-   1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one;-   6-chloro-8-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine;-   6-chloro-7-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine;-   8-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine;-   7-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine;-   N,N-dimethyl-2-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]ethylenamine;-   N,N-dimethyl-2-(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)ethylenamine;-   3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde;-   3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde;-   N,N-dimethyl-2-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]ethylenamine;-   2-[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-N,N-dimethylethylenamine;-   3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde;-   N,N-dimethyl-2-(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)ethylenamine;-   2-(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-N,N-dimethylethylenamine;-   2-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-N,N-dimethylethylenamine;-   3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde;-   methyl 3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate;-   6-chloro[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde;-   methyl 6-chloro[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate;-   (6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)(methoxy)methanol;-   [6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl](methoxy)methanol;-   1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde;-   4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one;-   1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde;-   4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methyl}pyrrolidin-2-one;-   1-(2-fluoroindolizin-3-yl)methanamine;-   4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one;-   1-{[6-[(2,4-dimethoxybenzyl)amino]-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   2-cyclopropyl-7-hydroxypyrazolo[1,5-a]pyrimidin-5(4H)-one;-   5,7-dichloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine;-   5,7-dichloro-2-cyclopropyl-6-methylpyrazolo[1,5-a]pyrimidine;-   5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine;-   5-chloro-2-cyclopropyl-6-methylpyrazolo[1,5-a]pyrimidine;-   1-(chloromethyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylic    acid;-   ethyl 3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoate;-   ethyl 2-formyl-3-(2-oxo-4-propylpyrrolidin-1-yl)propanoate;-   2-benzyl-4-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2,4-dihydro-3H-pyrazol-3-one.

In a further aspect, the present invention concerns also the use of acompound of formula I or a pharmaceutically acceptable salt thereof forthe manufacture of a medicament for the treatment of neurological andother disorders such as mentioned above.

In particular, the present invention concerns the use of a compound offormula I or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment of epilepsy, Parkinson'sdisease, dyskinesia, migraine, tremor, essential tremor, bipolardisorders, chronic pain, neuropathic pain, or bronchial, asthmatic orallergic conditions.

The methods of the invention comprise administration to a mammal(preferably human) suffering from above mentioned conditions ordisorders, of a compound according to the invention in an amountsufficient to alleviate or prevent the disorder or condition.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing 3 to 3000 mg,preferably 25 to 500 mg of active ingredient per unit dosage form.

The term “treatment” as used herein includes curative treatment andprophylactic treatment.

By “curative” is meant efficacy in treating a current symptomaticepisode of a disorder or condition.

By “prophylactic” is meant prevention of the occurrence or recurrence ofa disorder or condition.

The term “epilepsy” as used herein refers to a chronic neurologiccondition characterised by unprovoked, recurrent epileptic seizures. Anepileptic seizure is the manisfestation of an abnormal and excessivesynchronised discharge of a set of cerebral neurons; its clinicalmanifestations are sudden and transient. The term “epilepsy” as usedherein can also refer to a disorder of brain function characterised bythe periodic occurrence of seizures. Seizures can be “nonepileptic” whenevoked in a normal brain by conditions such as high fever or exposure totoxins or “epileptic” when evoked without evident provocation.

The term “seizure” as used herein refers to a transient alteration ofbehaviour due to the disordered, synchronous, and rhythmic firing ofpopulations of brain neurones.

The term “Parkinsonian symptoms” relates to a syndrome characterised byslowlyness of movement (bradykinesia), rigidity and/or tremor.Parkinsonian symptoms are seen in a variety of conditions, most commonlyin idiopathic parkinsonism (i.e. Parkinson's Disease) but also followingtreatment of schizophrenia, exposure to toxins/drugs and head injury. Itis widely appreciated that the primary pathology underlying Parkinson'sdisease is degeneration, in the brain, of the dopaminergic projectionfrom the substantia nigra to the striatum. This has led to thewidespread use of dopamine-replacing agents (e.g.L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine agonists) assymptomatic treatments for Parkinson's disease and such treatments havebeen successful in increasing the quality of life of patients sufferingfrom Parkinson's disease. However, dopamine-replacement treatments dohave limitations, especially following long-term treatment. Problems caninclude a wearing-off of the anti-parkinsonian efficacy of the treatmentand the appearance of a range of side-effects which manifest as abnormalinvoluntary movements, such as dyskinesias.

The term “dyskinesia” is defined as the development in a subject ofabnormal involuntary movements. This appears in patients withHuntington's disease, in Parkinson's disease patients exposed to chronicdopamine replacement therapy, and in Schizophrenia patients exposed tochronic treatment with neuroleptics. Dyskinesias, as a whole, arecharacterised by the development in a subject of abnormal involuntarymovements. One way in which dyskinesias may arise is as a side effect ofdopamine replacement therapy for parkinsonism or other basalganglia-related movement disorders.

The term “migraine” as used herein means a disorder characterised byrecurrent attacks of headache that vary widely in intensity, frequency,and duration. The attacks are commonly unilateral and are usuallyassociated with anorexia, nausea, vomiting, phonophobia, and/orphotophobia. In some cases they are preceded by, or associated with,neurological and mood disturbances. Migraine headache may last from 4hours to about 72 hours. The International Headache Society (IHS, 1988)classifies migraine with aura (classical migraine) and migraine withoutaura (common migraine) as the major types of migraine. Migraine withaura consists of a headache phase preceded by characteristic visual,sensory, speech, or motor symptoms. In the absence of such symptoms, theheadache is called migraine without aura.

The term “bipolar disorders” as used herein refers to those disordersclassified as Mood Disorders according to the Diagnostic and StatisticalManual of Mental Disorders, 4th edition (Diagnostic and StatisticalManual of Mental Disorders (DSM-IV™), American Psychiatry Association,Washington, D.C., 1994). Bipolar disorders are generally characterisedby spontaneously triggered repeated (i.e. at least two) episodes inwhich the patient's hyperexcitability, activity and mood aresignificantly disturbed, this disturbance consisting on some occasionsof an elevation of mood and increased energy and activity (mania orhypomania), and in other occasions a lowering of mood and decreasedenergy and activity (depression). Bipolar disorders are separated intofour main categories in the DSM-IV (bipolar I disorder, bipolar IIdisorder, cyclothymia, and bipolar disorders not otherwise specified).

The term “manic episode”, as used herein refers to a distinct periodduring which there is an abnormally and persistently elevated,expansive, or irritable mood with signs of pressured speech andpsychomotor agitation.

The term “hypomania”, as used herein refers to a less extreme manicepisode, with lower grade of severity.

The term “major depressive episode”, as used herein refers to a periodof at least 2 weeks during which there is either depressed mood or theloss of interest or pleasure in nearly all activities with signs ofimpaired concentration and psychomotor retardation.

The term “mixed episode”, as used herein refers to a period of time(lasting at least 1 week) in which the criteria are met both for a manicepisode and for a major depressive episode nearly every day.

The term “chronic pain” as used herein refers to the condition graduallybeing recognised as a disease process distinct from acute pain.Conventionally defined as pain that persists beyond the normal time ofhealing, pain can also be considered chronic at the point when theindividual realises that the pain is going to be a persistent part oftheir lives for the foreseeable future. It is likely that a majority ofchronic pain syndromes involves a neuropathic component, which isusually harder to treat than acute somatic pain.

The term “neuropathic pain” as used herein refers to pain initiated by apathological change in a nerve which signals the presence of a noxiousstimulus when no such recognisable stimulus exists, giving rise to afalse sensation of pain. In other words, it appears that the pain systemhas been turned on and cannot turn itself off.

The term “tics” refers to common and often disabling neurologicaldisorders. They are frequently associated with behaviour difficulties,including obsessive-compulsive disorder, attention deficit hyperactivitydisorder and impulse control. Tics are involuntary, sudden, rapid,repetitive, nonrhythmic stereotype movements or vocalizations. Tics aremanifested in a variety of forms, with different durations and degreesof complexity. Simple motor tics are brief rapid movements that ofteninvolve only one muscle group. Complex motor tics are abrupt movementsthat involve either a cluster of simple movements or a more coordinatedsequence of movements. Simple vocal tics include sounds such asgrunting, barking, yelping, and that clearing. Complex vocal ticsinclude syllables, phrases, repeating other people's words and repeatingone's own words.

The activity of the compounds of formula I, or their pharmaceuticallyacceptable salts, as anticonvulsants can be determined in the audiogenicseizure model. The objective of this test is to evaluate theanticonvulsant potential of a compound by means of audiogenic seizuresinduced in sound-susceptible mice, a genetic animal model with reflexseizures. In this model of primary generalised epilepsy, seizures areevoked without electrical or chemical stimulation and the seizure typesare, at least in part, similar in their clinical phenomenology toseizures occurring in man (Loscher W. & Schmidt D., Epilepsy Res.(1998), 2, 145-181; Buchhalter J. R., Epilepsia (1993), 34, S31-S41).Results obtained with compounds of formula I are indicative of a strongpharmacological effect.

Another assay indicative of potential anticonvulsant activity is bindingto levetiracetam binding site (LBS) as hereinafter described. As setforth in U.S. patent application Ser. Nos. 10/308,163 and 60/430,372 LBShas been identified as belonging to the family of SV2 proteins. As usedherein reference to “LBS” is to be understood as including reference toSV2.

Activity in any of the above-mentioned indications can of course bedetermined by carrying out suitable clinical trials in a manner known toa person skilled in the relevant art for the particular indicationand/or in the design of clinical trials in general.

For treating diseases, compounds of formula I or their pharmaceuticallyacceptable salts may be employed at an effective daily dosage andadministered in the form of a pharmaceutical composition.

Therefore, another embodiment of the present invention concerns apharmaceutical composition comprising an effective amount of a compoundof formula I or a pharmaceutically acceptable salt thereof incombination with a pharmaceutically acceptable diluent or carrier.

To prepare a pharmaceutical composition according to the invention, oneor more of the compounds of formula I or a pharmaceutically acceptablesalt thereof is intimately admixed with a pharmaceutical diluent orcarrier according to conventional pharmaceutical compounding techniquesknown to the skilled practitioner.

Suitable diluents and carriers may take a wide variety of formsdepending on the desired route of administration, e.g., oral, rectal,parenteral or intranasal.

Pharmaceutical compositions comprising compounds according to theinvention can, for example, be administered orally, parenterally, i.e.,intravenously, intramuscularly or subcutaneously, intrathecally, byinhalation or intranasally.

Pharmaceutical compositions suitable for oral administration can besolids or liquids and can, for example, be in the form of tablets,pills, dragees, gelatin capsules, solutions, syrups, chewing-gums andthe like.

To this end the active ingredient may be mixed with an inert diluent ora non-toxic pharmaceutically acceptable carrier such as starch orlactose. Optionally, these pharmaceutical compositions can also containa binder such as microcrystalline cellulose, gum tragacanth or gelatine,a disintegrant such as alginic acid, a lubricant such as magnesiumstearate, a glidant such as colloidal silicon dioxide, a sweetener suchas sucrose or saccharin, or colouring agents or a flavouring agent suchas peppermint or methyl salicylate.

The invention also contemplates compositions which can release theactive substance in a controlled manner. Pharmaceutical compositionswhich can be used for parenteral administration are in conventional formsuch as aqueous or oily solutions or suspensions generally contained inampoules, disposable syringes, glass or plastics vials or infusioncontainers.

In addition to the active ingredient, these solutions or suspensions canoptionally also contain a sterile diluent such as water for injection, aphysiological saline solution, oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents, antibacterial agents suchas benzyl alcohol, antioxidants such as ascorbic acid or sodiumbisulphite, chelating agents such as ethylene diamine-tetra-acetic acid,buffers such as acetates, citrates or phosphates and agents foradjusting the osmolarity, such as sodium chloride or dextrose.

These pharmaceutical forms are prepared using methods which areroutinely used by pharmacists.

The amount of active ingredient in the pharmaceutical compositions canfall within a wide range of concentrations and depends on a variety offactors such as the patient's sex, age, weight and medical condition, aswell as on the method of administration. Thus the quantity of compoundof formula I in compositions for oral administration is at least 0.5% byweight and can be up to 80% by weight with respect to the total weightof the composition.

In accordance with the invention it has also been found that thecompounds of formula I or the pharmaceutically acceptable salts thereofcan be administered alone or in combination with other pharmaceuticallyactive ingredients. Non-limiting examples of such additional compoundswhich can be cited for use in combination with the compounds accordingto the invention are antivirals, antispastics (e.g. baclofen),antiemetics, antimanic mood stabilizing agents, analgesics (e.g.aspirin, ibuprofen, paracetamol), narcotic analgesics, topicalanesthetics, opioid analgesics, lithium salts, antidepressants (e.g.mianserin, fluoxetine, trazodone), tricyclic antidepressants (e.g.imipramine, desipramine), anticonvulsants (e.g. valproic acid,carbamazepine, phenyloin), antipsychotics (e.g. risperidone,haloperidol), neuroleptics, benzodiazepines (e.g. diazepam, clonazepam),phenothiazines (e.g. chlorpromazine), calcium channel blockers,amphetamine, clonidine, lidocaine, mexiletine, capsaicin, caffeine,quetiapine, serotonin antagonists, β-blockers, antiarrhythmics,triptans, ergot derivatives and amantadine.

Of particular interest in accordance with the present invention arecombinations of at least one compound of formula I or a pharmaceuticallyacceptable salt thereof and at least one compound inducing neuralinhibition mediated by GABA_(A) receptors. The compounds of formula Iexhibit a potentiating effect on the compounds inducing neuralinhibition mediated by GABA_(A) receptors enabling, in many cases,effective treatment of conditions and disorders under reduced risk ofadverse effects.

Examples of compounds inducing neural inhibition mediated by GABA_(A)receptors include the following: benzodiazepines, barbiturates,steroids, and anticonvulsants such as valproate, viagabatrine, tiagabineor pharmaceutical acceptable salts thereof.

Benzodiazepines include the 1,4-benzodiazepines, such as diazepam andclonazepam, and the 1,5-benzodiazepines, such as clobazam. Preferredcompound is clonazepam.

Barbiturates include phenobarbital and pentobarbital. Preferred compoundis phenobarbital.

Steroids include adrenocorticotropic hormones such as tetracosactideacetate, etc.

Anticonvulsants include hydantoins (phenyloin, ethotoin, etc),oxazolidines (trimethadione, etc.), succinimides (ethosuximide, etc.),phenacemides (phenacemide, acetylpheneturide, etc.), sulfonamides(sulthiame, acetoazolamide, etc.), aminobutyric acids (e.g.gamma-amino-beta-hydroxybutyric acid, etc.), sodium valproate andderivatives, carbamazepine and so on.

Preferred compounds include valproic acid, valpromide, valproatepivoxil, sodium valproate, semi-sodium valproate, divalproex,clonazepam, phenobarbital, vigabatrine, tiagabine, amantadine.

For the preferred oral compositions, the daily dosage is in the range 3to 3000 milligrams (mg) of compounds of formula I.

In compositions for parenteral administration, the quantity of compoundof formula I present is at least 0.5% by weight and can be up to 33% byweight with respect to the total weight of the composition. For thepreferred parenteral compositions, the dosage unit is in the range 3 mgto 3000 mg of compounds of formula I.

The daily dose can fall within a wide range of dosage units of compoundof formula I and is generally in the range 3 to 3000 mg. However, itshould be understood that the specific doses can be adapted toparticular cases depending on the individual requirements, at thephysician's discretion.

The LBS binding compounds provided by this invention and labeledderivatives thereof may be useful as standards and reagents indetermining the ability of tested compounds (e.g., a potentialpharmaceutical) to bind to the LBS receptor.

Labeled derivatives of LBS ligands provided by this invention may alsobe useful as radiotracers for positron emission tomography (PET) imagingor for single photon emission computerized tomography (SPECT).

The present invention therefore further provides labelled ligands astools to screen chemical libraries for the discovery of potentialpharmaceutical agents, in particular for treatment and prevention of theconditions set forth herein, on the basis of more potent binding toLBS/SV2 proteins, for localizing SV2 proteins in tissues, and forcharacterizing purified SV2 proteins. SV2 proteins include SV2A, SV2B,and SV2C whereby SV2A is the binding site for the anti-seizure druglevetiracetam and its analogs. The SV2 isoforms SV2A, SV2B, or SV2C canbe derived from tissues, especially brain, from any mammal species,including human, rat or mice. Alternately the isoforms may be clonedversions of any mammalian species, including human, rat, and mice,heterologously expressed and used for assays. The screening methodcomprises exposing brain membranes, such as mammalian or human brainmembranes, or cell lines expressing SV2 proteins or fragments thereof,especially SV2A, but including SV2B and SV2C, to a putative agent andincubating the membranes or proteins or fragments and the agent withlabelled compound of formula I. The method further comprises determiningif the binding of the compound of formula I to the protein is inhibitedby the putative agent, thereby identifying binding partners for theprotein. Thus, the screening assays enable the identification of newdrugs or compounds that interact with LBS/SV2. The present inventionalso provides photoactivable ligands of SV2/LBS.

The labelled-ligands can also be used as tools to assess theconformation state of SV2 proteins after solubilization, purificationand chromatography. The labelled-ligands may be directly or indirectlylabeled. Examples of suitable labels include a radiolabel, such as ³H, afluorescent label, an enzyme, europium, biotin and other conventionallabels for assays of this type.

Screening assays of the present invention include methods of identifyingagents or compounds that compete for binding to the LBS (especiallySV2A). Labelled compounds of formula I are useful in the methods of theinvention as probes in assays to screen for new compounds or agents thatbind to the LBS (especially SV2A). In such assay embodiments, ligandscan be used without modification or can be modified in a variety ofways; for example, by labelling, such as covalently or non-covalentlyjoining a moiety which directly or indirectly provides a detectablesignal. In any of these assays, the materials can be labelled eitherdirectly or indirectly. Possibilities for direct labelling include labelgroups such as: radiolabels including, but not limited to, [³H], [¹⁴C],[³²P], [³⁵S] or [¹²⁵I], enzymes such as peroxidase and alkalinephosphatase, and fluorescent labels capable of monitoring the change influorescence intensity, wavelength shift, or fluorescence polarization,including, but not limited to, fluorescein or rhodamine. Possibilitiesfor indirect labelling include biotinylation of one constituent followedby binding to avidin coupled to one of the above label groups or the useof anti-ligand antibodies. The compounds may also include spacers orlinkers in cases where the compounds are to be attached to a solidsupport. To identify agents or compounds which compete or interact withlabelled ligands according to the invention for binding to the LBS(especially SV2A), intact cells, cellular or membrane fragmentscontaining SV2A or the entire SV2 protein or a fragment comprising theLBS of the SV2 protein can be used. The agent or compound may beincubated with the cells, membranes, SV2 protein or fragment prior to,at the same time as, or after incubation with L059 or an analog orderivative thereof. Assays of the invention may be modified or preparedin any available format, including high-throughput screening (HTS)assays that monitor the binding of L059 or the binding of derivatives oranalogs thereof to SV2 or to the LBS of the SV2 protein. In many drugscreening programs which test libraries of compounds, high throughputassays are desirable in order to maximize the number of compoundssurveyed in a given period of time. Such screening assays may use intactcells, cellular or membrane fragments containing SV2 as well ascell-free or membrane-free systems, such as may be derived with purifiedor semi-purified proteins. The advantage of the assay with membranefragment containing SV2 or purified SV2 proteins and peptides is thatthe effects of cellular toxicity and/or bioavailability of the testcompound can be generally ignored, the assay instead being focusedprimarily on the effect of the drug on the molecular target as may bemanifest in an inhibition of, for instance, binding between twomolecules. The assay can be formulated to detect the ability of a testagent or compound to inhibit binding of labeled ligand according to theinvention to SV2 or a fragment of SV2 comprising the LBS or of L059, orderivatives or analogs thereof, to SV2 or a fragment of SV2 comprisingthe LBS. The inhibition of complex formation may be detected by avariety of techniques such as filtration assays, Flashplates (PerkinElmer, scintillation proximity assays (SPA, Amersham Biosciences). Forhigh-throughput screenings (HTS), scintillation proximity assay is apowerful method which uses microspheres coated with biological membranesand requires no separation or washing steps.

Labelled ligands are also useful for assessing the conformational stateof SV2 after solubilization, purification, and chromatography. Moreover,the present invention provides photoactivable versions of the ligandsfor labelling and detection in biological samples. The photoactivableligands may also be used to localize and purify SV2 from tissues,isolated cells, subcellular fractions and membranes. The photoactivablecould also be used for SV2 cross-linking and identification of bindingdomains of LBS ligands.

EXAMPLES

The following examples are provided for illustrative purposes. Unlessspecified otherwise in the examples, characterization of the compoundsis performed according to the following methods:

NMR spectra are recorded on a BRUKER AC 250 Fourier Transform NMRSpectrometer fitted with an Aspect 3000 computer and a 5 mm ¹H/¹³C dualprobehead or BRUKER DRX 400 FT NMR fitted with a SG Indigo² computer anda 5 mm inverse geometry ¹H/¹³C/¹⁵N triple probehead. The compound isstudied in DMSO-d₆ (or CDCl₃) solution at a probe temperature of 313 Kor 300 K and at a concentration of 20 mg/ml. The instrument is locked onthe deuterium signal of DMSO-d₆ (or CDCl₃). Chemical shifts are given inppm downfield from TMS taken as internal standard.

HPLC analyses are performed using one of the following systems:

-   -   an Agilent 1100 series HPLC system mounted with an INERTSIL ODS        3 C18, DP 5 μm, 250×4.6 mm column. The gradient ran from 100%        solvent A (acetonitrile, water, H₃PO₄ (5/95/0.001, v/v/v)) to        100% solvent B (acetonitrile, water, H₃PO₄ (95/5/0.001, v/v/v))        in 6 min with a hold at 100% B of 4 min. The flow rate is set at        2.5 ml/min. The chromatography is carried out at 35° C.    -   a HP 1090 series HPLC system mounted with a HPLC Waters Symmetry        C18, 250×4.6 mm column. The gradient ran from 100% solvent A        (MeOH, water, H₃PO₄ (15/85/0.001M, v/v/M)) to 100% solvent B        (MeOH, water, H₃PO₄ (85/15/0.001 M, v/v/M)) in 10 min with a        hold at 100% B of 10 min. The flow rate is set at 1 ml/min. The        chromatography is carried out at 40° C.

Mass Spectrometric Measurements in LC/MS Mode are Performed as Follows:HPLC Conditions

Analyses are performed using a WATERS Alliance HPLC system mounted withan INERTSIL ODS 3, DP 5 μm, 250×4.6 mm column.

The gradient ran from 100% solvent A (acetonitrile, water, TFA(10/90/0.1, v/v/v)) to 100% solvent B (acetonitrile, water, TFA(90/10/0.1, v/v/v)) in 7 min with a hold at 100% B of 4 min. The flowrate is set at 2.5 ml/min and a split of 1/25 is used just before APIsource.

MS Conditions

Samples are dissolved in acetonitrile/water, 70/30, v/v at theconcentration of about 250 μgr/ml. API spectra (+ or −) are performedusing a FINNIGAN (San Jose, Calif., USA) LCQ ion trap mass spectrometer.APCI source operated at 450° C. and the capillary heater at 160° C. ESIsource operated at 3.5 kV and the capillary heater at 210° C. Massspectrometric measurements in DIP/EI mode are performed as follows:samples are vaporized by heating the probe from 50° C. to 250° C. in 5min. EI (Electron Impact) spectra are recorded using a FINNIGAN (SanJose, Calif., USA) TSQ 700 tandem quadrupole mass spectrometer. Thesource temperature is set at 150° C.

Mass spectrometric measurements on a TSQ 700 tandem quadrupole massspectrometer (Finnigan MAT, San Jose, Calif., USA) in GC/MS mode areperformed with a gas chromatograph model 3400 (Varian, Walnut Creek,Calif., USA) fitted with a split/splitless injector and a DB-5MSfused-silica column (15 m×0.25 mm I.D., 1 μm) from J&W Scientific(Folsom, Calif., USA). Helium (purity 99.999%) is used as carrier gas.The injector (CTC A200S autosampler) and the transfer line operate at290 and 250° C., respectively. Sample (1 μl) is injected in splitlessmode and the oven temperature is programmed as follows: 50° C. for 5min., increasing to 280° C. (23° C./min) and holding for 10 min. The TSQ700 spectrometer operates in electron impact (EI) or chemical ionization(Cl/CH₄) mode (mass range 33-800, scan time 1.00 sec). The sourcetemperature is set at 150° C. Also used is a 1100 LCMSD VL series,single quadrupole, APCI or API-ES ionization (Agilent Technologies, USA)equipped with the following HPLC columns: Luna C18 5 um 100×4.6 mm(Phenomenex, USA) or Hi-Q C18 5 um 100×4.6 mm (Peeke Scientific, USA) orBetasil C18 10 um 150×4.6 mm (ThermoHypersil, USA). GC/MS are also donewith GC 6890 equipped with FID and 5973 MSD, single quadrupole, EIionization (Agilent Technologies, USA) equipped with column: HP-5MS30m×0.25 mm×0.25 um (Agilent Technologies, USA).

Specific rotation is recorded on a Perkin-Elmer 341 polarimeter. Theangle of rotation is recorded at 25° C. on 1% solutions in MeOH. Forsome molecules, the solvent is CH₂Cl₂ or DMSO, due to solubilityproblems.

Melting points are determined on a Büchi 535 or 545 Tottoli-typefusionometre, and are not corrected, or by the onset temperature on aPerkin Elmer DSC 7.

Preparative chromatographic separations are performed on silicagel 60Merck, particle size 15-40 μm, reference 1.15111.9025, using Novasepaxial compression columns (80 mm i.d.), flow rates between 70 and 150ml/min. Amount of silicagel and solvent mixtures as described inindividual procedures.

Preparative Chiral Chromatographic separations are performed on a DAICELChiralpak AD 20 μm, 100*500 mm column using an in-house build instrumentwith various mixtures of lower alcohols and C5 to C8 linear, branched orcyclic alkanes at ±350 ml/min. Solvent mixtures as described inindividual procedures.

The following abbreviations are used in the examples:

AcOEt Ethyl acetateBINAP (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

CH₃CN Acetonitrile CH₂Cl₂ Dichloromethane

DCE 1,2-dichloroethane

DMF N,N-Dimethylformamide

MTBE Methyl tert-butyl ether

NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimideSTAB NaBH(OAc)₃

TFA Trifluoroacetic acid

THF Tetrahydrofuran

The following examples illustrate how the compounds covered by formula(I) can be synthesized.

Example 1 Synthesis of1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 148

1.1. Synthesis of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2.

A solution of 4-propylpyrrolidin-2-one x1 (30 g, 0.236 mol), aqueousformaldehyde (37%, 3.5 eq, 0.826 mol, 71 ml), and potassium hydroxyde(0.05 eq, 0.012 mol, 0.662 g) in 150 ml of ethanol is refluxed for 24hours. After evaporation of the solvent under reduced pressure, thecrude product is poured in saturated NaHCO₃ aqueous solution and thenextracted with CH₂Cl₂. The cumulated organic layers are dried overMgSO₄, filtered and evaporated under reduced pressure to yield compound1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 as a colorless oil.

Yield: 100%.

LC-MS (MH⁺): 158.

1.2. Synthesis of1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 148.

A solution of 5-nitro-1H-indole x3 (100 mg, 1 eq, 0.62 mmol),1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (108.27 mg, 1 eq, 0.62mmol), paratoluenesulfonic acid (11 mg, 0.1 eq, 0.062 mmol) in 5 ml oftoluene is refluxed for 4 hours. After cooling to room temperature, thesolvent is removed under reduced pressure and the crude product ispurified by preparative chromatography on reverse phase (gradient:H₂O/CH₃CN/TFA: 95/5/0.1 (v/v/v) to 5/95/0.1 (v/v/v)) affording1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 148 as acolorless oil.

Yield: 44%.

LC-MS (MH⁺): 302.

Compounds 142, 143, 144, 145, 146, 147, 149 and 150 may be synthesizedaccording to the same method.

Example 2 Synthesis of1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 153

2.1. Synthesis of (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamatex6

To a solution of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (4 g,25.44 mmol) and triethylamine (1.2 eq, 30.53 mmol, 3.089 g, 4.26 ml) inCH₂Cl₂ (25 ml) is added dropwise a solution of diethylcarbamyl chloride(1.1 eq, 27.99 mmol, 3.795 g, 3.55 ml) in CH₂Cl₂ (5 ml) at roomtemperature. The reaction mixture is allowed to react under agitationand inert atmosphere overnight. Hydrolysis (15 ml of water), extraction(CH₂Cl₂), drying of the combinated organic layers (MgSO₄), filtrationand solvent evaporation under reduced pressure gives(2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6 (100%) whichis used without any further purification.

¹H NMR δ_(H) (250 MHz, CDCl₃): 0.93 (3H, t), 1.22 (6H, q), 1.4 (4H, m),2.10 (1H, dd), 2.34 (1H, quint), 2.53 (1H, dd), 3.20 (1H, dd), 3.45 (4H,m), 3.65 (1H, dd), 4.78 (2H, q).

2.2. Synthesis of1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 153

A solution of indole x4 (117 mg, 1 eq, 1 mmol), 4-propylpyrrolidin-2-onex1 (127 mg, 1 eq, 1 mmol), 2-furaldehyde x5 (0.33 ml, 4 eq, 4 mmol) and(2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6 (25 mg, 0.1eq, 0.1 mmol) in acetonitrile (3 ml) is heated 30 minutes in a microwaveapparatus (Biotage, 150 W, 130° C.). After cooling to room temperature,the solvent is removed under reduced pressure, and the crude mixture ispurified by preparative chromatography on silicagel (CH₂Cl₂) leading to1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 153 as a brownsolid.

Yield: 28%.

LC-MS (MH⁺): 323.

Compounds 151, 152 and 154 may be synthesized according to the samemethod.

Example 3 Synthesis of4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one 231

To a solution of commercially available 1H-pyrrolo[2,3-b]pyridine x7(20.31 mmol, 1.2 eq, 3.19 g) dissolved TFA (25 ml) is added1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (16.93 mmol, 1 eq, 2 g).The mixture is heated at 70° C. overnight. The solvent is thenevaporated under reduce pressure. CH₂Cl₂ (600 ml) is then added to theresidue, and the resulting organic solution is washed with a saturatedaqueous solution of sodium carbonate (200 ml). The organic phase is thendried over MgSO₄ and the volatiles are removed under reduced pressure.The product is purified by chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 97/3/0.3 (v/v/v)) and recristallized inacetonitrile.4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one 231 isobtained as a white solid.

Yield: 13%.

LC-MS (MH⁺): 258.

Compounds 232, 233, 234, 244 and 246 may be synthesized according to thesame method.

Example 4 Synthesis of1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one 7

A solution of 2-aminopyridine x8 (1 g, 1 eq, 10.6 mmol) andbromomalonaldehyde x9 (1.6 g, 1 eq, 10.6 mmol) in 1.4-dioxane (20 ml) isrefluxed for 3 days (Imidazo[1,2-a]pyridine-3-carbaldehyde x10 is formedin situ and not isolated). After cooling to room temperature,triethylamine (2.96 ml, 2 eq, 21.25 mmol), methyl4-amino-3-phenylbutanoate hydrochloride x1 (2.44 g, 1 eq, 10.6 mmol) andethanol (10 ml) are successively added. The mixture is then allowed toreact during 3 days at room temperature. The reaction mixture is pouredon ice, and organic solvents are removed under reduced pressure. Theresulting aqueous layer is extracted by CH₂Cl₂ and the cumulated organiclayers are dried over MgSO₄, filtered, and condensed under reducedpressure. The crude product is purified by preparative chromatography onsilicagel (CH₂Cl₂/iPrOH: 97/3 (v/v)), then recristallized in ethylacetate leading to1-(imidazol-[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one 7 as awhite powder.

Yield: 8%.

LC-MS (MH⁺): 292.

Methyl 3-(aminomethyl)hexanoate hydrochloride x12, useful for examplefor the synthesis of compound 3, may be prepared by esterification ofthe corresponding acid according to any method known to the personskilled in the art.

Compounds 3, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 22, 23, 28, 29,155 and 156 may be synthesized as described for compound 7.

Example 5 Synthesis of1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one184

5.1. Synthesis of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine x14.

To a solution of 3-methyl-1H-pyrazol-5-amine a12 (64.8 mmol, 1 eq, 6.3g) in EtOH (100 ml), in the presence of PTSA, is addedbromomalonaldehyde x9 (64.8 mmol, 1 eq, 9.79 g). The mixture is heatedat 80° C. for 12 hours. The solvent is evaporated under reduce pressureand the residue purified by chromatography on silicagel (hexane/AcOEt:93/7 (v/v)). 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine x14 is obtainedas a white solid (4.04 g).

Yield: 30%.

LC-MS (MH⁺): 212/214.

The following compounds may be synthesized according to the same method:

x15 2-methylpyrazolo[1,5-a]- LC-MS (MH⁺): 134 pyrimidine x166-bromo-2-(2-thienyl)pyrazolo[1,5- LC-MS (MH⁺): 280/282 a]pyrimidine x176-bromo-2-phenylpyrazolo[1,5- LC-MS (MH⁺): 274/276 a]pyrimidine x186-bromo-2-cyclopropylpyrazolo[1,5- LC-MS (MH⁺): 238/240 a]pyrimidine x196-bromo-2-tert-butylpyrazolo[1,5- LC-MS (MH⁺): 254/256 a]pyrimidine x206-chloro-2-phenylpyrazolo[1,5- LC-MS (MH⁺): 230/232 a]pyrimidine

5.2. Synthesis of6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x21.

POCl₃ (1.84 mmol, 1.3 eq, 172 μl) is added dropwise to DMF (1 ml) at 0°C. and the resulting solution is stirred at 0° C. during 30 minutes.Then, a solution of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine x14 (1.415mmol, 1 eq, 300 mg) in DMF (1 ml) is added and the mixture is stirredfor 30 minutes at room temperature. The reaction is quenched with water(100 ml). The resulting solid is filtered and washed with water to give200 mg of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x21as a solid.

Yield: 59%.

LC-MS (MH⁺): 240/242.

The following compounds may be synthesized according to the same method:

x22 2-methylpyrazolo[1,5-a]pyrimidine-3- LC-MS (MH⁺): 162 carbaldehydex23 6-bromo-2-(2-thienyl)pyrazolo[1,5- LC-MS (MH⁺):a]pyrimidine-3-carbaldehyde 308/310 x246-bromo-2-cyclopropylpyrazolo[1,5- LC-MS (MH⁺):a]pyrimidine-3-carbaldehyde 266/268 x252-(2-furyl)pyrazolo[1,5-a]pyrimidine-3- LC-MS (MH⁺): 214 carbaldehydex26 6-methyl-2-phenylpyrazolo[1,5- LC-MS (MH⁺): 238a]pyrimidine-3-carbaldehyde x27 5-methyl-2-phenylpyrazolo[1,5- LC-MS(MH⁺): 238 a]pyrimidine-3-carbaldehyde x28 2-(2-thienyl)pyrazolo[1,5-LC-MS (MH⁺): 230 a]pyrimidine-3-carbaldehyde x29 6-methylimidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde x30 6-(4-methylphenyl)imidazo[2,1-LC-MS (MH⁺): 244 b][1,3,4]thiadiazole-5-carbaldehyde

5.3. Synthesis of1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one184

Ethyl 3-(aminomethyl)hexanoate hydrochloride x31 is obtained byesterification of the corresponding carboxylic acid according to anymethod known to the person skilled in the art.

To a solution of6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x21 (0.83 mmol,1 eq, 200 mg) in MeOH (10 ml), is added ethyl 3-(aminomethyl)hexanoatehydrochloride x31 (0.916 mmol, 1.1 eq, 192 mg) and the resultingsolution is stirred at room temperature for 5 minutes. Triethylamine(0.916 mmol, 1.1 eq, 128 □l) is then added and the mixture is heated at65° C. for 1 hour. After this time 1 hour, sodium borohydride is added(0.916 mmol, 1.1 eq, 34 mg). The reaction mixture is then heated at 65°C. for 2 hours. Water (100 ml) is added and the resulting mixture isextracted with CH₂Cl₂ (3×100 ml). The combined organic layers arecombined, washed with brine (100 ml) and dried over MgSO₄. Volatiles areremoved under reduce pressure and purified by chromatography onsilicagel (CH₂Cl₂/MeOH/NH₄OH: 9713/0.3) to give 130 mg of1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one184 as a solid.

Yield: 45%.

LC-MS (MH⁺): 351/353.

Compounds 88, 89, 91, 92, 185, 187 and 193 may be synthesized asdescribed for compound 184.

Example 6 Synthesis of5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one35

6.1. Synthesis of6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x35.

A solution of 6-chloro-3-aminopyridazine x34 (3.16 g, 1 eq, 24.2 mmol)and 3-bromo-1,1,1-trifluorobutan-2-one (5 g, 1 eq, 24.4 mmol) in1,2-dimethoxyethane (100 ml) is refluxed during 17 hours. After coolingto room temperature and filtration, the solvent is removed under reducedpressure and the crude mixture is purified by preparative chromatographyon silicagel (CH₂Cl₂/MeOH/NH₄OH: 98/2/0.2 (v/v/v)) leading to6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x35.

Yield: 60%.

LC-MS (MH⁺): 236/238.

6.2. Synthesis of3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x36

A mixture of6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x35 (3.45g, 1 eq, 14.64 mmol), N-bromosuccinimide (NBS; 2.87 g, 1.1 eq, 16.11mmol) and azo-bis-iso-butyronitrile (AIBN; 240 mg, 0.1 eq, 1.5 mmol) inacetonitrile (50 ml) is refluxed for 2 hours. After cooling to roomtemperature, the solvent is removed under reduced pressure and the crudeproduct is purified by preparative chromatography on silicagel (CH₂Cl₂)affording3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazinex36.

Yield: 35%.

LC-MS (MH⁺): 315/317.

6.3. Synthesis of5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one35

To a suspension of 5-chloro-1,3-dihydro-2H-indol-2-one x32 (30 g, 1 eq,0.1754 mol) in water (240 ml), is added barium hydroxyde (75.15 g, 2.5eq, 0.4385 mol) at room temperature. The resulting suspension is heatedat reflux for 17 hours, cooled to 0° C. and a 6 N hydrochloric acidsolution (113 ml) is added (until pH 8). The resulting solution isheated at reflux for 30 minutes, cooled to 70° C. in 2 hours and then to50° C. for 15 hours. The resulting suspension is progressively cooled to0° C. and the solid collected by filtration. Subsequent washing of thesolid by water (2×90 ml) and drying in vacuum oven (70° C.) furnishedbarium bis[(2-amino-5-chlorophenyl)acetate] x33 as a colorless powder(yield: 73%).

A mixture of barium bis[(2-amino-5-chlorophenyl)acetate] x33 (1.13 g,1.5 eq, 3.34 mmol) and3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x36(0.7 g, 1 eq, 2.22 mmol) in tetrahydrofuran (50 ml) is refluxed for 9days. After cooling to room temperature, the reaction mixture isfiltered over celite and concentrated under reduced pressure, the crudeproduct is purified by preparative chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 99/1/0.1 (v/v/v)) and recristallized in toluene toyield5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one35 as a white powder.

Yield: 25%.

LC-MS (MH⁺): 401/403/405.

Example 7 Synthesis of1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one 229

7.1 Synthesis of1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 228

A solution of 4-propylpyrrolidin-2-one x1 (0.50 g, 3.93 mmol, 1 eq) and2-chloro-5-(chloromethyl)pyridine x37 (0.64 g, 3.93 mmol, 1 eq) inacetonitrile (3 ml) is heated at 50° C. NaH (60% dispersion in oil, 158mg, 3.93 mmol, 1 eq) and acetonitrile (5 ml) are added and the solutionis stirred for 8 h at 50° C. The mixture is then poured on ice/water andthe aqueous phase is extracted with CH₂Cl₂. The combined organic phasesare dried over MgSO₄, filtered and concentrated to dryness. The crudeproduct is purified by chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH:99/1/0.1 (v/v/v)) to afford 790 mg of1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 228.

Yield: 80%.

LC-MS (MH⁺): 253/255.

Compound 224 and racemic 1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one may besynthesized as described for compound 228.

Enantiomers 225 and 226 may be prepared from racemic1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one by separation by chiralchromatography.

7.2. Synthesis of1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one 229.

To a solution of1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 228 (100 mg,0.396 mmol, 1 eq), benzylamine (65 μl, 0.61 mmol, 1.6 eq) and potassiumcarbonate (274 mg, 1.98 mmol, 5 eq) is added a stirred solution ofPd₂(dba)₃ (Tris(dibenzylideneacetone)dipalladium(0), 18 mg, 0.02 mol,0.05 eq) and BINAP (13 mg, 0.02 mol, 0.05 eq) in 2 ml of 1,4-dioxane.The mixture is heated at reflux for 36 h, filtered and concentrated. Thecrude product is dissolved in water and extracted three times withCH₂Cl₂. The organic phase is dried over MgSO₄, filtered and evaporatedto dryness. The crude is purified by chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 97/3/0.3 (v/v/v)) to afford 14 mg of1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one 229.

Yield: 11%.

LC-MS (MH⁺): 324.

Example 8 Synthesis of1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one252

8.1. Synthesis of 4-(2,3,5-trifluorophenyl)pyrrolidin-2-one x38

4-(2,3,5-trifluorophenyl)pyrrolidin-2-one x38 is synthesized fromnitromethane and ethyl 3-(2,3,5-trifluorophenyl)acrylate according tothe methodology described in Kenda B. et al., J. Med. Chem. (2004), 47,530-549.

8.2. Synthesis of1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one250

In a 250 ml three-necked flask fitted with a magnetic stirrer and anaddition funnel, under inert atmosphere, 1.04 g (0.026 mol) of sodiumhydride (60% dispersion in oil, washed with hexane) is suspended in THF(80 ml) at 0° C. Compound x38 (4 g, 0.0183 mol), dissolved in THF, isadded dropwise and the resulting mixture is stirred at room temperaturefor 0.5 h. A solution of 2-chloro-5-(chloromethyl)-1,3-thiazole x39(3.12 g, 0.0186 mol) in THF is added and the solution is stirred at 50°C. overnight. The mixture is concentrated to dryness, dissolved inCH₂Cl₂, brine is added and the aqueous is extracted twice with CH₂Cl₂.The combined organic phases are dried over MgSO₄, filtered andevaporated. The crude product is purified by preparative chromatographyon silicagel (CH₂Cl₂/MeOH/NH₄OH: 99.5/0.45/0.05 (v/v/v)) to afford 3.7 gof pure1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one250.

Yield: 57%.

LC-MS (MH⁺): 347/349.

8.3. Synthesis of1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one252

In a 50 ml sealed vessel,1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one250 (0.1 g, 0.3 mmol) is dissolved in MeOH (3 ml). Sodium methoxide (3mg, 0.06 mmol) and a solution of methylamine (0.09 g, 3 mmol) in MeOHare added. The vessel is closed and heated to 95° C. for 48 h. Thereaction mixture is cooled to room temperature, the solvent isevaporated and the residue is taken up in CH₂Cl₂ and water. The aqueousphase is extracted twice with CH₂Cl₂, the combined organic phases arewashed with brine, dried over MgSO₄, filtered and concentrated in vacuo.The crude product is recrystallized from AcOEt to afford 185 mg of1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one252.

Yield: 57%.

LC-MS (MH⁺): 342.

Example 9 Synthesis of4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one 247

9.1. Synthesis of 1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-onex40.

1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-one x40 is synthesizedfrom ethyl bromoacetate and 4-propylpyrrolidin-2-one according to themethodology described in Kenda B. et al. (J. Med. Chem. (2004), 47,530-49).

9.2. Synthesis of 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide x41.

In a 250 ml three necked flask fitted with a magnetic stirrer, hydrazinehydrate (5.78 g, 0.18 mol, 3 eq) is added to a solution of1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-one x40 (11.99 g, 60.29mmol) in EtOH (125 ml). The mixture is heated 4 h at reflux, cooled downto room temperature, diluted with brine and extracted with CH₂Cl₂. Thecombined organic phases are dried over MgSO₄, filtered and evaporated toafford 11.0 g of 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide x41.

Yield: 83%.

LC-MS (MH⁺): 200.

9.3. Synthesis of4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one 247

In a 25 ml vessel, a mixture of2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide x41 (0.5 g, 2.5 mmol)and acetic acid (5 ml) is stirred overnight at room temperature andconcentrated to dryness. The residue is dissolved in AcOEt, washed witha saturated solution of NaHCO₃, water and brine. The aqueous phase issaturated with NaCl, extracted with a mixture of CH₂Cl₂ and MeOH (9/1(v/v)), resaturated with Na₂CO₃ and re-extracted with CH₂Cl₂. Thecombined organic phases are dried over MgSO₄, filtered and evaporated.The crude intermediate (2.3 mmol) is dissolved in 40 ml of dioxane, P₂S₅(0.51 g, 2.3 mmol) is added at 0° C. and the mixture is stirred at roomtemperature during 9.5 h. The solvent is evaporated and the crudeproduct is purified by column chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 95/4.5/0.5 (v/v/v)) to give 88 mg of4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one 247.

Yield: 16%.

LC-MS (MH⁺): 226.

Example 10 Synthesis of1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-onehydrochloride 119

10.1. Synthesis of4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x44.

In a 500 ml, three-necked flask fitted with a magnetic stirrer and areflux condenser under inert atmosphere, ethyl 4-amino-3-phenylbutanoatehydrochloride x42 (synthesized as described in patent applicationEP1265862, 6.2 g, 38 mmol), 1-trityl-1H-imidazole-4-carbaldehyde x43(Dolensky B., Kirk K. L., Collect. Czech. Chem. Commun. (2002), 67,1335-1344; 8.2 g, 36.1 mmol) and MeOH (150 ml) are stirred at roomtemperature. Triethylamine (3.9 ml, 41.85 mmol) and NaBH₄ (1.06 g, 41.8mmol) are added by portions. The mixture is stirred at 45° C. for 3 h,then at room temperature overnight. CH₂Cl₂ (300 ml) and water (300 ml)are added, the aqueous phase is extracted with CH₂Cl₂ (2×200 ml). Thecombined organic phases are washed with a saturated solution of NH₄Cl(2×150 ml), dried, filtered and concentrated in vacuo. The crude productis recrystallized from AcOEt to afford4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x44.

Yield: 36%.

LC-MS (MH⁺): 484.

The following compounds may be synthesized according to the same method:

x45 4-propyl-1-[(1-trityl-1H-imidazol-4- LC-MS (MH⁺): 450yl)methyl]-pyrrolidin-2-one x46 1-[(1-trityl-1H-imidazol-4- LC-MS (MH⁺):408 yl)methyl]pyrrolidin-2-one x474-(2,3,5-trifluorophenyl)-1-[(1-trityl-1H- LC-MS (MH⁺): 538imidazol-4-yl)methyl]pyrrolidin-2-one

10.2. Synthesis of1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-onehydrochloride 119

In a 50 ml, three-necked flask fitted with a magnetic stirrer, underinert atmosphere,4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x44 (2 g,4.1 mmol) is dissolved in CH₃CN (20 ml) and MeI (283 μL, 4.5 mmol) isadded. The mixture is stirred at room temperature and two additionalportions of MeI (283 μl and 500 μl) are added after 40 h and 46 h. Afterstirring for 16 h at room temperature, the mixture is concentrated anddissolved in a 1/1 mixture of AcOH and water. After stirring at roomtemperature for 48 h, the mixture is filtered and evaporated to dryness(by azeotropic distillation with toluene). The residue is dissolved in asolution of HCl at pH 1 (25 ml) and extracted with CH₂Cl₂ (3×50 ml). Theaqueous phase is brought at pH 10 by adding solid K₂CO₃ and extractedagain with CH₂Cl₂ (3×50 ml). Combined organic phases are dried overMgSO₄, filtered and concentrated to give 1 g of crude product which ispurified by chromatography on silicagel (60 g of SiO₂,CH₂Cl₂/EtOH/NH₄OH: 94/5.4/0.6 (v/v/v)) to give 0.5 g of1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one. Thisfree base is treated with a 3.6 M solution of HCl (5 ml), and theresulting solid is recrystallized in CH₃CN to lead to1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-onehydrochloride 119.

Yield: 33%.

LC-MS (MH⁺): 256.

Compounds 116, 121 and1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-onex48 may be synthesized as described for compound 119.

Example 11 Synthesis of1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one129

Synthesis of1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one129 is performed by chlorination of1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 121 with2 equivalents of N-chlorosuccinimide under standard conditions known bythe person skilled in the art.

LC-MS (MH⁺): 290/292/294.

Example 12 Synthesis ofN-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide124

12.1. Synthesis of ethyl{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetatehydrochloride x49

In a 50 ml, three-necked flask fitted with a magnetic stirrer underinert atmosphere, ethylbromoacetate (560 μl, 4.95 mmol) is added to asolution of4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x45 (1.5g, 3.3 mmol) in 10 ml of acetonitrile. The mixture is stirred at 40° C.for 3 h, 1.65 mmol of ethylbromoacetate is added and stirring is pursuedfor 48 h at room temperature. The mixture is concentrated in vacuo, 20ml of a 1/1 mixture of acetic acid and water is added and the mixture isstirred at room temperature overnight. The mixture is filtered, thesolvent is evaporated and the residue is dissolved in 25 ml of dilutedHCl (pH 1). The aqueous phase is washed with CH₂Cl₂, basified to pH 10by addition of solid Na₂CO₃ and extracted three times with CH₂Cl₂. Thecombined organic phases are dried over MgSO₄, filtered and concentratedto dryness. The crude product is purified by tin layer chromatography onpreparative plates (CH₂Cl₂/EtOH: 90/10 (v/v)) to give 275 mg of ethyl{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetate(30%). Ethyl{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetatehydrochloride x49 is obtained by treatment with a solution of HCl inEt₂O and recrystallization from CH₃CN/AcOEt.

Yield: 16%.

LC-MS (MH⁺): 294.

12.2. Synthesis of{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetic acidx50

In a 250 ml, three necked flask fitted with a magnetic stirrer, ethyl{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetatehydrochloride x49 (5.19 g, 0.018 mol) is dissolved in 2M HCl (150 ml)and heated at 40° C. for 20 h. The reaction mixture is evaporated todryness to afford the crude acid x50 (6.19 g) that is used as such inthe next step.

LC-MS (MH⁺): 266.

12.3. Synthesis ofN-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide124

In a 10 ml, three necked flask fitted with a magnetic stirrer, underinert atmosphere,{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetic acidx50 (0.1 g, 0.33 mmol) is dissolved in DMF (1 ml). Triethylamine (0.1ml, 0.66 mmol), benzylamine (37 μl, 0.33 mmol) and TBTU (0.16 g, 0.33mmol) are added and the mixture is stirred for 0.5 h at roomtemperature. An additional amount of benzylamine (0.0165 mmol) is addedand stirring is continued overnight. The solvent is evaporated and theresidue is purified by chromatography on silicagel (AcOEt/MeOH/NH₄OH:90/9/1 (v/v/v)). The product is treated with a methanolic solution ofHCl and the obtained solid is recrystallized from acetonitrile to affordN-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide124.

Yield: 43%.

LC/MS (MH⁺): 355.

Example 13 Synthesis of1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one167

13.1. Synthesis of 4-iodo-3,5-dimethyl-1H-pyrazole x52.

In a 250 ml reaction vessel, 3,5-dimethyl-1H-pyrazole x51 (0.5 g, 5mmol), 12 (0.79 g, 30 mmol) and CAN (1.71 g, 3 mmol) are dissolved in 70ml of CH₃CN and stirred at room temperature for 16 h. The solvent isevaporated, the residue dissolved in AcOEt and washed with a 10% aqueoussolution of Na₂S₂O₃ and brine. The aqueous phase is re-extracted withAcOEt and the combined organic phases are dried over Na₂SO₄, filteredand concentrated to dryness to afford 1.15 g (100%) of crude4-iodo-3,5-dimethyl-1H-pyrazole x52, which is used in the next stepwithout further purification.

LC-MS (MH⁺): 223.

13.2. Synthesis of4-iodo-3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole x53.

In a 50 ml reaction vessel under argon, a solution of crude4-iodo-3,5-dimethyl-1H-pyrazole x52 (1.15 g, 5.2 mmol) in 25 ml of dryCH₂Cl₂ is added to 4-methylbenzenesulfonyl chloride (1.18 g, 6.2 mmol).Pyridine (0.42 ml, 5.2 mmol) is added and the mixture is stirred for 16h at room temperature. The organic phase is washed with water, driedover MgSO₄, filtered and concentrated. The residue is purified by columnchromatography on silicagel (CH₂Cl₂/hexane: 70/30 (v/v)) to afford4-iodo-3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole x53 (1.44g).

Yield: 74%.

LC-MS (MH⁺): 377.

The following compounds may be synthesized according to the same method:

x54 4-iodo-3-methyl-1-[(4- LC-MS (MH⁺): 363methylphenyl)sulfonyl]-1H-pyrazole x554-iodo-1-[(4-methylphenyl)sulfonyl]-1H- LC-MS (MH⁺): 349 pyrazole

13.3. Synthesis of3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x56

In a reaction vessel under inert atmosphere,4-iodo-3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole x53 (1.44g, 3.8 mmol) is dissolved in dry THF (10 ml) and cooled down to −73° C.A 2M solution of isopropylmagnesiumchloride in THF (9.6 mmol, 4.8 ml) isadded dropwise and the mixture is stirred at −73° C. for 1 h. Then 0.44ml of DMF (5.7 mmol) are added and the solution stirred at roomtemperature overnight. DMF (1.9 mmol) is further added and stirring iscontinued for 16 h. The reaction mixture is quenched with a saturatedsolution of NH₄Cl, extracted three times with CH₂Cl₂, the organic phaseis washed with brine, dried over MgSO₄, filtered and concentrated invacuo to give 0.88 g of crude3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehydex56, which is used in the next step without any further purification.

Yield: 82%.

LC-MS (MH⁺): 279.

The following compounds may be synthesized according to the same method:

x57 3-methyl-1-[(4-methylphenyl)sulfonyl]-1H- LC-MS (MH⁺): 265pyrazole-4-carbaldehyde x58 1-[(4-methylphenyl)sulfonyl]-1H- LC-MS(MH⁺): 251 pyrazole-4-carbaldehyde x59 1-[(4-methylphenyl)sulfonyl]-1H-LC-MS (MH⁺): 251 pyrazole-5-carbaldehyde

13.4. Synthesis of1-({3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-onex61

In a 100 ml three-necked flask fitted with a magnetic stirrer, underinert atmosphere,3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x56(0.87 g, 3.1 mmol) and ethyl 4-amino-3-(2,3,5-trifluorophenyl)butanoatehydrochloride x60 (synthesized from nitromethane and ethyl3-(2,3,5-trifluorophenyl)acrylate by the same methodology as describedin Kenda et al., J. Med. Chem. (2004), 47, 530-49; 0.94 g, 3.1 mmol) aredissolved in CH₂Cl₂ (30 ml). Triethylamine (0.86 ml, 6.3 mmol) andNaBH(OAc)₃ (1.33 g, 6.3 mmol) are added and the heterogeneous mixturebecame a solution. After 16 h at room temperature, two additionalportions of NaBH(OAc)₃ are added (1.6 mmol after 16 h and 3.2 mmol after48 h) and 1.6 mmol of triethylamine are added after 24 h stirring atroom temperature. The reaction is quenched with water and the aqueousphase is extracted three times with diethylether. The combined organicphases are washed with brine, dried over MgSO₄, filtered andconcentrated to dryness. The crude product is purified by columnchromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH: 95/4.5/0.5 (v/v/v)) toafford 0.83 g of1-({3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-onex61.

Yield: 55%.

LC-MS (MH⁺): 478.

Compounds 158, 159, 160, 161, 163, 165, 169, 175, 176, 179, 180 and1-({3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-onex62 may be synthesized as described for compound x61.

13.5. Synthesis of1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one167

In a 100 ml flask fitted with a magnetic stirrer and a reflux condenserunder inert atmosphere,1-({3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-onex61 (0.83 g, 1.7 mmol) is dissolved in THF (40 ml). A 1 M solution oftetrabutylammonium fluoride in THF (1.7 ml, 1.7 mmol) is added and themixture is heated at 85° C. for 48 h. The solvent is evaporated and theresidue is dissolved in water. The aqueous phase is extracted six timeswith diethylether and the combined organic phases are dried over MgSO₄,filtered and concentrated in vacuo. The crude product is purified bypreparative chromatography on silicagel and recrystallized from AcOEt togive 77 mg of1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one167.

Yield: 14%.

LC-MS (MH⁺): 324.

Compounds 164, 168 and 181 may be synthesized as described for compoundx61.

Enantiomers 171 and 172 may be obtained after separation by chiralchromatography (Chiralpak AD; hexane/iPrOH/Et₂NH: 90/10/01 (v/v/v)) ofracemic compound 164.

Example 14 Synthesis of1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one170

In a 25 ml, three-necked flask fitted with a magnetic stirrer, underinert atmosphere, 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.136g, 0.77 mmol) is added dropwise to a suspension of AlCl₃ (0.033 g, 0.25mmol) in TCE at 0° C. In another 25 ml, three-necked flask fitted with amagnetic stirrer and reflux condenser under inert atmosphere,1-methyl-1H-pyrazol-5-amine x64 (0.05 g, 0.51 mmol) is dissolved in TCE(10 ml) and the mixture is heated at 65° C. At this temperature, thesolution containing compound x63 and AlCl₃ is added dropwise and themixture is heated at 80° C. for 16 h. Water and CH₂Cl₂ are added, the pHis brought up to 8 with sodium bicarbonate and the aqueous phase isextracted with CH₂Cl₂. The combined organic phases are washed withbrine, dried over MgSO₄, filtered and concentrated. The crude product ispurified by preparative chromatography on silicagel, then by preparativechromatography on reverse phase to afford 19 mg of1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one170.

Yield: 16%.

LC-MS (MH⁺): 237.

Example 15 Synthesis of1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one183

15.1. Synthesis of1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one182

1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one182 is prepared as for compound x61 starting from ethyl4-amino-3-(2,3,5-trifluorophenyl)butanoate hydrochloride x60 and4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde x65.

LC-MS (MH⁺): 388/390.

15.2. Synthesis of1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one183

In a 250 ml pressure jar, under inert atmosphere,1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one182 (0.41 g, 1 mmol) is dissolved in MeOH (50 ml). Pd on charcoal (82mg, 20% w/w) is added and the mixture is hydrogenated under a pressureof 40 psi at room temperature for 3 h. The mixture is filtered on Celiteand concentrated to dryness. The residue is purified by columnchromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH: 98/1.8/0.2 (v/v/v)) andrecrystallized from diisopropylether to afford 0.18 g of1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one183.

Yield: 58%.

LC-MS (MH⁺): 310.

Example 16 Synthesis of 1-(pyridazin-4-ylmethyl)pyrrolidin-2-one 222

16.1. Synthesis of ethyl 4-[(pyridazin-4-ylmethylene)amino]butanoatex68.

In a 25 ml, three-necked flask fitted with a magnetic stirrer underinert atmosphere, pyridazine-4-carbaldehyde x66 (0.93 g, 8.6 mmol) andethyl 4-aminobutanoate hydrochloride x67 (1.58 g, 9.5 mmol) aredissolved in CHCl₃ (15 ml). Triethylamine (1.3 ml, 9.5 mmol) and MgSO₄(2 g) are added and the mixture is stirred at room temperature for 4 h.The mixture is filtered, washed with water, dried over MgSO₄ andconcentrated to give 1.92 g (100%) of crude ethyl4-[(pyridazin-4-ylmethylene)amino]butanoate x68, which is used in thenext step without further purification.

¹H NMR (250 MHz, DMSO): 1.16 (t, 3H), 1.9 (qt, 2H), 2.38 (t, 2H), 3.67(t, 2H), 4.05 (q, 2H), 7.89 (m, 1H), 8.44 (s, 1H), 9.34 (m, 1H), 9.47(s, 1H).

16.2. Synthesis of ethyl 4-[(pyridazin-4-ylmethyl)amino]butanoate x69.

In a 50 ml, three-necked flask fitted with a magnetic stirrer, underinert atmosphere, ethyl 4-[(pyridazin-4-ylmethylene)amino]butanoate x68(1.92 g, 8.7 mmol) is dissolved in MeOH (20 ml). Acetic acid (1.1 ml,8.7 mmol), sodium acetate (0.71 g, 8.7 mmol) and NaCNBH₃ (1.1 g, 17.4mmol) are added and the reaction temperature rises to 47° C. The mixtureis stirred for 1.25 h at room temperature, evaporated and the resultingresidue is purified by column chromatography on silicagel(CH₂Cl₂/EtOH/NH₄OH: 96/5.4/0.6 (v/v/v)) to afford 0.72 g as a mixture ofethyl 4-[(pyridazin-4-ylmethyl)amino]butanoate x69 and1-(pyridazin-4-ylmethyl)pyrrolidin-2-one 47 in a 75/25 ratio, which isused as such in the next step.

LC-MS (MH⁺): 224.

16.3. Synthesis of 1-(pyridazin-4-ylmethyl)pyrrolidin-2-one 222

In a 25 ml, three-necked flask fitted with a magnetic stirrer and areflux condenser under inert atmosphere, the mixture described in 16.2(0.72 g, 75/25 (w/w), 3.4 mmol)) is dissolved in acetic acid (10 ml) andbrought to reflux for 4.5 h. The solvent is removed by azeotropicdistillation with toluene, the crude product is purified bychromatography on silicagel (CH₂Cl₂/MeOH: 92/8 (v/v)) and recrystallizedfrom toluene to give 127 mg of 1-(pyridazin-4-ylmethyl)pyrrolidin-2-one222.

Yield: 21%.

LC-MS (MH⁺): 178.

Example 17 Synthesis of5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one 227

17.1. Synthesis of 5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1H-indolex72.

In a 50 ml, three-necked flask fitted with a magnetic stirrer underinert atmosphere, 5-chloro-1H-indole x70 (1.13 g, 7.43 mmol) isdissolved in dry DMF (20 ml). At 0° C., NaH (327 mg, 8.18 mmol, 60% inmineral oil) is added and the mixture is stirred at this temperature for0.3 h. A solution of 3-(chloromethyl)-2-fluoropyridine x71 (obtainedfrom (2-fluoropyridin-3-yl)methanol and SOCl₂ (1.3 g, 8.92 mmol)) in DMF(5 ml) is then added and stirring is continued for 0.5 h at 0° C. Thereaction mixture is poured on ice and the aqueous phase is extractedthree times with AcOEt. The combined organic phases are dried overMgSO₄, filtered and concentrated. Purification by chromatography onsilicagel (Hexane/AcOEt:9/1 (v/v)) affords5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1H-indole x72 as a solid (1.13g).

Yield: 59%.

¹H NMR (250 MHz, DMSO): 5.5 (s, 2H), 6.5 (s, 1H), 7.1 (dd, 1H), 7.3 (m,1H), 7.4-7.6 (m, 3H), 7.6 (d, 1H), 8.1 (d, 1H).

17.2. Synthesis of3,3-dibromo-5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onex73

In a 100 ml, three-necked flask fitted with a magnetic stirrer underinert atmosphere, pyridine hydrobromide perbromide (4.04 g, 12.65 mmol)is added to a suspension of5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1H-indole x72 (1.10 g, 4.22mmol) in t-BuOH. The mixture is stirred at room temperature for 0.5 h.Water is added and the aqueous phase is extracted three times withAcOEt. The combined organic phases are dried over MgSO₄, filtered andconcentrated to dryness to afford 1.79 g of3,3-dibromo-5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onex73, which is used in the next step without further purification.

Yield: 98%.

¹H NMR (250 MHz, DMSO): 5.15 (s, 2H), 7.20 (d, 1H), 7.50 (m, 1H), 7.56(dd, 1H), 7.90-7.97 (m, 2H), 8.30 (d, 1H).

17.3. Synthesis of5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one 227

In a 50 ml, three-necked flask fitted with a magnetic stirrer underinert atmosphere,3,3-dibromo-5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onex73 (1.79 g, 4.12 mmol) is dissolved in AcOH (20 ml) and, at 0° C.,powdered zinc (2.7 g, 41.2 mmol) is added. The mixture is stirred for 10min at room temperature, filtered on Celite and concentrated to dryness.The residue is purified by chromatography on silicagel (Hexane/AcOEt:6/4(v/v)) to give 104 mg of5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one227.

Yield: 35%.

LC-MS (DIP) (M+1): 276/278.

Example 18 Synthesis of1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one 283

18.1. Synthesis of1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one x75.

A solution of commercially available 6-chloro-7H-purine x74 (0.5 g, 3.23mmol), 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (1 eq, 3.23 mmol,0.508 g), and (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6(0.1 eq, 83 mg, 0.32 mmol) in acetonitrile (5 ml) is heated 30 minutesin a microwave apparatus (Biotage, 150 W, 130° C.). After cooling toroom temperature, the solvent is removed under reduced pressure and thecrude product is purified by preparative chromatography leading to 600mg of pure 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-onex75.

Yield: 63%.

LC-MS (MH⁺): 294/296.

18.2. Synthesis of1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one 283.

A solution of intermediate x75 (600 mg, 2.04 mmol), ammonium formiate(644 mg, 5 eq, 10.21 mmol) and palladium on charcoal (10% wt, 109 mg,0.1 mmol) in a 1 to 1 mixture of THF and methanol (20 ml) is allowed toreact at ambient temperature for 16 hours. After filtration on celiteand solvent evaporation, the crude product is purified using preparativechromatography on silicagel to furnish a crude compound which isrecristallized in a mixture of CH₂Cl₂ and hexane to furnish1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one 283 as awhite crystalline product (320 mg).

Yield: 60%.

LC-MS (MH⁺): 260.

Example 19 Synthesis of1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one 268

19.1. Synthesis of 1-(aminomethyl)-4-propylpyrrolidin-2-one x76

A solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (41.34 g,0.235 mol) in toluene (350 ml) is added dropwise at −78° C. to liquidammonia (300 ml). At the end of the addition, the temperature is raisedslowly to room temperature, and ammonia of the crude mixture is allowedto distille at room temperature overnight. Filtration of the reactionmixture and subsequent evaporation lead to 55 g of the crude1-(aminomethyl)-4-propylpyrrolidin-2-one x76 which is used withoutfurther purification.

LC-MS (MH⁺): 157.

19.2. Synthesis of1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x77.

A mixture of 1-(aminomethyl)-4-propylpyrrolidin-2-one x76 (1 eq, 17.09mmol, 2.67 g), 2-chloro-3-nitropyridine (1 eq, 17.09 mmol, 2.709 g) andtriethylamine (1.1 eq, 18.8 mmol, 1.902 g, 2.62 ml) in dioxane (20 ml)is refluxed 48 h. After cooling, the crude mixture is filtrated and thedioxane is distilled under vacuum. The residue is purified bypreparative chromatography to afford 2.5 g of1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x77.

Yield: 53%.

LC-MS (MH⁺): 279.

19.3. Synthesis of1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x78.

Palladium on charcoal (10% wt, 0.478 g) is added to a solution of1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x77 (1eq, 2.5 g, 8.983 mmol) and NH₄CO₂H (5 eq, 44.9 mmol, 2.832 g) in waterand methanol (1/1 (v/v), 35 ml). The resulting slurry is kept underagitation during 16 hours at room temperature, then filtration overcelite and evaporation of the crude mixture afford 2.524 g of1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x78.

Yield: 100%.

¹H NMR (250 MHz, CDCl₃) δ ppm: 0.88 (3H, t); 1.26-1.38 (4H, m); 2.02(1H, dd); 2.28 (1H, quint); 2.47 (1H, dd); 3.22 (1H, dd), 3.37 (2H, s,broad); 3.73 (1H, dd); 5.02 (2H, d), 5.40 (1H, m, broad); 6.55 (1H, dd),6.85 (1H, dd), 7.67 (1H, dd).

19.4. 1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one268

A solution of1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x78 (1eq, 1.6 mmol, 300 mg), and para-toluenesulfonic acid (0.32 mmol, 0.2 eq,42 mg) in trimethyl orthoformate (15 ml) is allowed to react at roomtemperature for 3 days. After hydrolysis (20 ml of saturated NaHCO₃),extraction with AcOEt (2×10 ml), drying of the cumulated organic layersover MgSO₄, and filtration, the volatiles are removed under reducedpressure and the crude material is purified by preparativechromatography affording 250 mg of1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one 268.

Yield: 61%.

LC-MS (MH⁺): 259.

Example 20 Synthesis of1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one291

20.1. Synthesis of 5-bromo-1H-pyrazolo[3,4-b]pyridine x80.

A solution of 1H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) andbromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) isrefluxed for 2 hours. After cooling, the reaction mixture is stirred atroom temperature overnight. The solvent is removed under reducedpressure and the crude is purified using chiral chromatography affording5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (yield: 2.1%; LC-MS (MH⁺):198/200) and 6-bromopyrazolo[1,5-a]pyrimidine x81 (yield: 13.8%; LC-MS(MH⁺): 198/200).

20.2. Synthesis of1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one291

A solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (1 g, 1 eq, 5.04mmol) and 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (1.58 g, 2 eq,10.08 mmol) in trifluoroacetic acid (20 ml) is refluxed for 4 hours. Thereaction mixture is poured on crushed ice, on saturated NaHCO₃ aqueoussolution, and the aqueous phase is extracted with dichloromethane. Thecumulated organic layers are dried over MgSO₄, filtered, evaporatedunder reduced pressure. The crude product is purified by preparativechromatography on silicagel affording1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one291 as a white solid.

Yield: 7.8%.

LC-MS (MH⁺): 337/339.

Compound 265 may be synthesized according to the same method.

Example 21 Synthesis of 1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one297

In a three-necked flask fitted with a reflux condenser, a magneticstirrer, and under inert atmosphere, triazole (1.0 g, 14.5 mmol) isdissolved in THF (10 ml) at room temperature. Sodium hydride (0.64 g, 16mmol) is added by portions under efficient stirring. The temperatureraises to 31° C. The resulting mixture is refluxed,1-(chloromethyl)pyrrolidin-2-one (1.93 g, 14.5 mmol) is added, andfurther stirring is applied for 2 hours. The mixture is cooled down toroom temperature, diluted with CH₂Cl₂ and water, and concentrated todryness. The crude mixture is purified by chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 96/4/0.4) and recrystallized from toluene to afford0.59 g of 1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one 297.

Yield: 24.5%.

LC-MS (MH⁺): 167.

Example 22 Synthesis of1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one251

In a sealed tube fitted with a magnetic stirrer,1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one250 (0.3 g, 0.87 mmol) is dissolved in a mixture of THF (4 ml) and H₂O(0.1 ml). Dimethylamine (0.85 ml, 1.7 mmol) and LiOH.H₂O (0.043 g, 1mmol) are added and the mixture is stirred at room temperature for 12 hand heated at 50° C. overnight. Dimethylamine (3×3.4 mmol, then 1×5.1mmol) is added after 24 h, 48 h, 72 h and 96 h heating. THF isevaporated, the residue is dissolved in water and CH₂Cl₂, the pH of theaqueous phase is brought to 9 and the aqueous phase is extracted withCH₂Cl₂. The combined organic phases are dried over MgSO₄, filtered andconcentrated. The crude product is purified by chromatography onsilicagel and recrystallized from diisopropylether to afford 0.1 g of1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one251.

Yield: 32%.

LC-MS (MH⁺): 356.

Compound 253 may be synthesized according to the same method.

Example 23 Synthesis of5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1,3-thiazol-2(3H)-one254

Synthesis of5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1,3-thiazol-2(3H)-one250 is performed by hydrolysis of1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one254 with concentrated HCl (37% w/w) in classical conditions know by theperson skilled in the art.

Yield: 5%.

LC-MS (MH⁺): 329.

Example 24 Synthesis of1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one 6 and1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one 249

24.1. Synthesis of 2-chloro-3-(2-oxopyrrolidin-1-yl)propanal x83

In a 250 ml, three-necked flask fitted with a magnetic stirrer,1-(hydroxymethyl)pyrrolidin-2-one x82 (15 g, 0.13 mol) is cooled to −10°C. Cold concentrated sulfuric acid (150 ml) is added dropwise. At thistemperature, 1,2-dichloroethene (46.73 g, 0.482 mol) is added while thetemperature is kept below 0° C. At the end of the addition the mixtureis stirred at 40° C. for 2 h. Water is added and the pH is adjusted withK₂CO₃. The aqueous phase is extracted with CH₂Cl₂, the combined organicphases are dried over MgSO₄, filtered and concentrated. The crude2-chloro-3-(2-oxopyrrolidin-1-yl)propanal x83 is used in the next stepwithout any further purification.

24.2. Synthesis of 1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one248.

In a 500 ml, three-necked flask fitted with a magnetic stirrer andreflux condenser under inert atmosphere, crude2-chloro-3-(2-oxopyrrolidin-1-yl)propanal x83 (14.13 g, 0.08 mol) isdissolved in MeOH (150 ml). Thiourea (6.12 g, 0.08 mol) and potassiumiodide (catalytic amount) are added and the mixture is stirred at refluxfor 48 h. Thiourea (3.04 g, 0.04 mol) is added and the mixture is heatedfor another 72 h. The solvent is evaporated, the residue is purified bychromatography on silicagel (CH₂Cl₂/MeOH: 95/5 (v/v)) to afford threefractions of respectively 3.11 g (A), 0.470 g (B) and 2.45 g (C).Fraction B is recrystallized from EtOH to afford 143 mg of1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one 248.

Yield: 9%.

LC-MS (MH⁺): 198.

24.3. Synthesis of 1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one 249

In a 250 ml, three-necked flask fitted with a magnetic stirrer andreflux condenser under inert atmosphere,1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one 248 (1.04 g, 6.8mmol) is dissolved in THF 20 ml). Isoamylnitrite (1.59 g, 13.6 mmol) isadded and the mixture is heated at reflux for 3 h. The solvent isevaporated and the residue is purified by chromatography on silicagel(CH₂Cl₂/MeOH: 95/5 (v/v)) to give 405 mg of1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one 249.

Yield: 31%.

GC-MS (M+1): 182.

Example 25 Synthesis of1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile127

25.1. Synthesis of S-ethyl 4-cyano-1-methyl-1H-imidazole-5-carbothioatex85.

In a 1 l, three-necked flask fitted with a magnetic stirrer and a refluxcondenser under inert atmosphere,4-cyano-1-methyl-1H-imidazole-5-carboxylic acid x84 (24.5 g, 0.162 mol)and CH₂Cl₂ (500 ml) are stirred at room temperature. To this suspension,ethanethiol (13.2 ml, 0.178 mol) and DMAP (1.98 g, 0.016 mol) are added,followed by DCC (36.77 g, 0.178 mol) in two portions. The temperaturerises to 35° C. and the mixture is stirred at room temperature for 16 h.Ethanethiol (0.0324 mol) is further added and stirring is continuedovernight. The mixture is filtered and the solvent is evaporated. Theresidue is purified by chromatography on silicagel (Hexane/AcOEt:6/4(v/v)) to give 29.5 g of S-ethyl4-cyano-1-methyl-1H-imidazole-5-carbothioate x85.

Yield: 93%.

¹H RMN (250 MHz, DMSO): 1.37 (t, 3H), 3.13 (q, 2H), 3.91 (s, 3H), 7.56(s, 1H).

25.2. Synthesis of 5-formyl-1-methyl-1H-imidazole-4-carbonitrile x86

In a 750 ml, three-necked flask fitted with a magnetic stirrer underinert atmosphere, S-ethyl 4-cyano-1-methyl-1H-imidazole-5-carbothioatex85 (8 g, 0.041 mol) is dissolved in 400 ml of acetone. Pd on charcoal(1.6 g) is added and the mixture is cooled to 0° C. Triethylsilane (13.1ml, 0.082 mol) is added dropwise and the mixture is stirred at 0° C. for0.5 h. The reaction is monitored by NMR. Three additional portions oftriethylsilane (0.041 mol, 0.041 mol and 0.0205 mol) are added over aperiod of 14 h, 17 h and 19 h respectively while stirring at 0° C. Themixture is filtered on Celite after complete consumption of startingproduct. The solvent is evaporated and the residue is purified twice bychromatography on silicagel (Hexane/AcOEt:6/4 (v/v)) to afford 3 g of5-formyl-1-methyl-1H-imidazole-4-carbonitrile x86.

Yield: 54%.

GC-MS (M+1): 135.

25.3. Synthesis of1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile127

1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile127 is prepared according to the method described in 10.1 starting from5-formyl-1-methyl-1H-imidazole-4-carbonitrile x86 and ethyl4-amino-3-(2,3,5-trifluorophenyl)butanoate hydrochloride x60.

Yield: 25.8%.

LC-MS (MH⁺): 335.

Compounds 117 and racemic 122 may be synthesized as described forcompound 127.

Example 26 Synthesis of1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-4-yl}methyl)-4-propylpyrrolidin-2-onetrifluoroacetate 111

In a 50 ml, three-necked flask fitted with a magnetic stirrer, a refluxcondenser and a dropping funnel under inert atmosphere, 1.56 g (3.5mmol) of 4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-onex45 is dissolved in acetonitrile (9 ml). To this solution is addeddropwise a mixture of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63(0.98 g, 5 mmol) in 9 ml of acetonitrile that is first brought to pH 8by adding triethylamine. The mixture is warmed to 75-80° C. during 32 h,the solvent is evaporated and the residue dissolved in acetic acid (10ml) and water (10 ml). The mixture is stirred overnight at roomtemperature, filtered and concentrated. The residue taken up with a HClsolution (pH 2) and extracted with diethyl ether. The aqueous phase isbrought to pH 8 with solid Na₂CO₃ and extracted with CH₂Cl₂. Thecombined organic phases are dried over MgSO₄, filtered and concentratedto dryness. After purification by chromatography on silicagel(MTBE/CH₂Cl₂/MeOH/NH₄OH: 45/45/9/1 (v/v/v/v)), the compound (0.4 g) isdissolved in CH₂Cl₂ (10 ml), treated with trifluoroacetic acid (80 μl),concentrated and recrystallized from THF/isopropanol to afford 0.23 g of1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-4-yl}methyl)-4-propylpyrrolidin-2-onetrifluoroacetate 111.

Yield: 11%.

LC-MS (MH⁺): 347.

Example 27 Synthesis of1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide123

In a 25 ml, three-necked flask fitted with a magnetic stirrer, a refluxcondenser and a dropping funnel under inert atmosphere, 150 mg (0.61mmol) of1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile122 is dissolved in MeOH (9 ml) with water (3 ml) and aqueous NaOH (35%w/w, 30 μl). The reaction mixture is refluxed 72 h, cooled down to roomtemperature and the solvent is evaporated to dryness. The crude reactionmixture is purified by preparative chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 96/3.6/0.4 (v/v/v/v)) and recristallized inCH₂Cl₂/hexane to afford1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide123 (0.07 g).

Yield: 43%.

LC-MS (MH⁺): 247.

Example 28 Synthesis of1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 126

28.1. Synthesis of 1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one110.

In a 50 ml reaction flask fitted with a magnetic stirrer,4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x45 (1.8g, 4 mmol) is dissolved in a 1/1 mixture of CH₃CO₂H/H₂O (30 ml) and thesolution is stirred for 36 h at room temperature. Most of the solventsare removed under vacuum and the residue is dissolved in 1N HCl anddiluted with CH₂Cl₂. The first organic phase is removed and pH of theaqueous phase is adjusted to 9 by addition of solid Na₂CO₃. Then CH₂Cl₂is added and the second organic phase is separated, dried over MgSO₄ andconcentrated to dryness, affording 730 mg of1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one 110.

Yield: 88%.

LC-MS (MH⁺): 208.

Compounds 115, 118 and1-(1H-imidazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one x87(LC-MS (MH⁺): 226) may be synthesized according to the same method.

Compound 139 is obtained in two steps following the experimentalprocedure of example 34 followed by reaction with MeI as described inexample 28.1.

28.2. Synthesis of1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 126.

In a 100 ml, three-necked flask fitted with a magnetic stirrer and underinert atmosphere, 1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one110 (500 mg, 2.4 mmol) is dissolved in a 1/1 mixture of CH₃CN/THF (40ml) and the solution is cooled to 0° C. N-chlorosuccinimide (410 mg, 3.1mmol) is added by portions while the temperature is maintained at 0° C.The mixture is stirred for 18 h at this temperature. Most of thesolvents are removed under vacuum and the residue is dissolved in 1N HCland diluted with CH₂Cl₂. The first organic phase is removed and pH ofthe aqueous phase is adjusted to 9 by addition of solid Na₂CO₃. ThenCH₂Cl₂ is added and the second organic phase is separated, dried overMgSO₄ and concentrated to dryness. Purification by preparativechromatography on silicagel (eluent: CH₂Cl₂/MeOH/NH₄OH: 95/05/0.5(v/v/v)) affords 440 mg of1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 126.

Yield: 76%.

LC-MS (MH⁺): 242/244.

Compounds 112, 131, 133, 135, 136, 137 and 140 may be synthesizedaccording to the same method.

1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one128 is obtained by bromination of1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 121 withN-bromosuccinimide using standard procedures known by any person skilledin the art.

Yield: 70%.

LC-MS (MH⁺): 300/302.

Compounds 113, 114, 132 and 138 may be synthesized according to the samemethod.

Example 29 Synthesis of1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile125

In a 2 l, three-necked flask fitted with a magnetic stirrer and refluxcondenser under inert atmosphere, DMAP (60.4 g, 0.495 mol) is dissolvedin DMF (900 ml) and the solution is cooled to 0° C. Cyanogen bromide(54.4 g, 0.495 mol) is added by portions while the temperature ismaintained between 0 and 10° C. The mixture is stirred for 0.5 h at thistemperature and a solution of1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 121 (36.5g, 0.165 mol) in DMF (500 ml) is added. The mixture is heated at 40° C.overnight. The DMAP-BrCN complex (0.165 mol) in 350 ml of DMF is addedat 5° C. (after being stirred for 1 h) and the mixture is heated at 45°C. overnight. One equivalent of the DMAP-BrCN complex in DMF (150 ml) isprepared again and added to the mixture at a temperature comprisedbetween 0° C. and 10° C. The mixture is stirred at 45° C. overnight. Thesolvent is evaporated, the residue is dissolved in AcOEt, then theorganic phase is washed with a saturated solution of NaHCO₃ and brine,dried over MgSO₄ and concentrated to dryness. Purification bypreparative chromatography on silicagel affords 13.5 g1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile125.

Yield: 33%.

LC-MS (MH⁺): 247.

Example 30 Synthesis of the two enantiomers of1-[1-(1H-imidazol-4-yl)propyl]pyrrolidine-2-one 106 and 107

30.1. Synthesis of 1-(1-trityl-1H-imidazol-4-yl)propan-1-ol x88

In a 100 ml, three-necked flask fitted with a magnetic stirrer, underinert atmosphere, ethyl iodide (1.1 ml, 0.0136 mol) is dissolved in Et₂O(25 ml). At −70° C., a 1.5 M solution of t-BuLi in pentane (17 ml, 0.026mol) is added dropwise. The mixture is stirred 0.3 h at this temperatureand 0.75 h at room temperature. A solution of1-trityl-1H-imidazole-4-carbaldehyde x43 (2 g, 0.00591 mole) in THF (25ml) is added dropwise at 0° C. The mixture is stirred for 1 h and pouredonto ice. HCl is added until the pH is slightly acid (pH: 3-5) and theaqueous phase is extracted twice with Et₂O. The combined organic phasesare dried over MgSO₄, filtered and concentrated to dryness. The crudeproduct is purified by chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH:95/4.5/0.5 (v/v/v)) to afford 1.21 g of1-(1-trityl-1H-imidazol-4-yl)propan-1-ol x88.

Yield: 56%.

LC-MS (MH⁺): 369.

30.2. Synthesis of 1-(1-trityl-1H-imidazol-4-yl)propan-1-one x89.

In a 50 ml three-necked flask fitted with a magnetic stirrer and areflux condenser under inert atmosphere,1-(1-trityl-1H-imidazol-4-yl)propan-1-ol x88 (1.21 g, 3.3 mmol) and MnO₂(2.85 g, 33 mmol) are dissolved in 20 ml of dioxane and the mixture isbrought to reflux for 1 h. The mixture is filtered on Celite and thesolvent is evaporated. Purification by chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 90/9/1 (v/v/v)) affords 0.96 g of pure1-(1-trityl-1H-imidazol-4-yl)propan-1-one x89.

Yield: 80%.

¹H RMN (250 MHz, DMSO): 1.05 (t, 3H), 2.9 (q, 2H), 7.25 (m, 6H), 7.5 (m,10), 7.6 (s, 1H).

30.3. Synthesis of ethyl4-{[1-(1-trityl-1H-imidazol-4-yl)propyl]amino}butanoate x90.

In a 100 ml, three-necked flask fitted with a magnetic stirrer, underinert atmosphere, ethyl 4-aminobutanoate hydrochloride a17 (1.75 g,0.0104 mol) is dissolved in MeOH (30 ml). Sodium acetate (1.28 g, 0.0156mol), a solution of 1-(1-trityl-1H-imidazol-4-yl)propan-1-one x89 (0.96g, 2.6 mmol) in a mixture of MeOH (7 ml) and Et₂O (20 ml), NaBH₃CN (0.15g, 2.34 mmol) and finally Na₂SO₄ are added. After stirring for 48 h atroom temperature, the mixture is poured on Et₂O/H₂O. The organic phaseis washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude ethyl4-{[1-(1-trityl-H-imidazol-4-yl)propyl]amino}butanoate x90 (0.814 g) isused in the next step without any further purification.

Yield: 65%.

LC-MS (MH⁺): 482.

The following compounds may be synthesized according to the same method:

x91 ethyl 3-{[(2-methyl-1-trityl-1H-imidazol-5- LC-MS (MH⁺): 468yl)methyl]amino}propanoate x92 ethyl3-{[(4-methyl-1-trityl-1H-imidazol-5- LC-MS (MH⁺): 468yl)methyl]amino}propanoate

30.4. Synthesis of the two enantiomers of1-[1-(1H-imidazol-4-yl)propyl]pyrrolidin-2-one 106 and 107

In a 25 ml, three-necked flask fitted with a magnetic stirrer and areflux condenser under inert atmosphere, a solution of ethyl4-{[1-(1-trityl-1H-imidazol-4-yl)propyl]amino}butanoate x90 (0.81 g,1.68 mmol) in acetic acid (10 ml) is brought to reflux for 48 h. Thesolvent is evaporated and the residue is purified by chromatography onsilicagel (CH₂Cl₂/MeOH/NH₄OH: 95/4.5/0.5 to 92/7.2/0.8 (v/v/v)). Theenantiomers are separated by chiral chromatography and recrystallizedfrom AcOEt to afford 106 (A-1§, 33 mg, yield: 48%) and 107 (B-1§, 37 mg,yield: 54%).

LC-MS (MH⁺): 194.

Compounds 108 and 109 may be synthesized according to the same method.

Example 31 Synthesis of1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one 120

31.1 Synthesis of 1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine x94

In a 250 ml, three-necked flask fitted with a magnetic stirrer, a refluxcondenser and under inert atmosphere,4-methoxy-1-methyl-1H-imidazole-5-carboxamide x93 (1.45 g, 9.5 mmol) isdissolved at room temperature in anhydrous THF (80 ml). Lithiumaluminium hydride (685 mg, 18 mmol) is added by portions while thetemperature is rising to 30° C. The mixture is stirred for 7 h at 60° C.and cooled down to room temperature. Then isopropanol is added and themixture is stirred for a further 16 hours at room temperature. First HCl37% (W/W) is added to the rectional mixture to reach pH 1, then 5 N KOHto adjust pH to 10. The solvents are removed under vacuum. The residueis dissolved in a mixture of CH₂Cl₂/MeOH (80/20), filtered through acelite pad and concentrated to dryness. Purification by preparativechromatography on silicagel (conditions: CH₂Cl₂/MeOH/NH₄OH: 90/10/1(v/v/v)) affords 500 mg of1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine x94.

Yield: 38%.

DIP (MH⁺): 141.

31.2. Synthesis of1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one 120

In a 50 ml, three-necked flask fitted with a magnetic stirrer, underinert atmosphere, 1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine x94(0.37 g, 2.62 mmol), Na₂SO₄ (0.37 g, 2.62 mmol) and powdered molecularsieves are stirred in CH₂Cl₂ (25 ml) at 0° C. At this temperature,powdered KOH (0.53 g, 9.44 mmol) and a solution of tetra-n-butylammonium bromide (48 mg, 0.13 mmol) in CH₂Cl₂ (5 ml) are added. Themixture is stirred for 0.25 h at 0° C. and 4-bromobutanoyl chloride (366μl, 3.14 mmol) is added dropwise. Stirring is continued for 2 h. Themixture is filtered on Celite and evaporated in vacuo. The residue isdissolved in DMF (25 ml) and NaH (60% dispersion in oil, 0.12 g, 3.14mmol) is added. The mixture is stirred at room temperature for 16 h. Anadditional portion of NaH (0.52 mmol) is added and the mixture isstirred for 4 more hours at room temperature. The mixture is thendiluted with 30 ml of CH₂Cl₂, filtered on Celite and concentrated todryness. The residue is purified by chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 95/4.5/0.5 (v/v/v)) and recrystallized fromdiisopropyl ether to afford 150 mg of1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one 120.

Yield: 27%.

LC-MS (MH⁺): 210.

Example 32 Synthesis of4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one 162

In a 250 ml, three-necked flask fitted with a magnetic stirrer underinert atmosphere, 20 ml of liquid ammonia is condensed and sodium isadded until the solution turns blue. A solution of1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one160 (1 g, 2.6 mmol) in THF (5 ml) is added and the mixture is stirred at−78° C. for 5 minutes. NH₄Cl and water are added, ammonia is evaporatedin vacuo and the aqueous phase is extracted with CH₂Cl₂. The combinedorganic phases are washed with brine, dried over MgSO₄, filtered andconcentrated to dryness. The residue is purified by preparativechromatography on C18 reversed phase (CH₃CN/H₂O/NH₄HCO₃, gradient) toafford 73 mg of 4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one 162.

Yield: 12%.

LC-MS (MH⁺): 242.

Example 33 Synthesis of1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one 173

33.1. Synthesis of sodium (2-aminophenyl)acetate x96.

In a 25 ml, three-necked flask fitted with a magnetic stirrer and areflux condenser, oxindole x95 (1 g, 7.5 mmol) and 15 ml of 4N NaOH(37.5 mmol) are heated at 100° C. overnight. This solution containing(2-aminophenyl)acetic acid x96 is used as such in the next step withoutfurther purification.

LC-MS (MH⁺): 152.

Barium bis[(2-amino-5-chlorophenyl)acetate] x97 is synthesized accordingto the same procedure (LC-MS (MH⁺): 186/188 and (M-H)⁻:184/186) startingfrom 5-chloro-1,3-dihydro-2H-indol-2-one.

33.2. Synthesis of 1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-onehydrate 173.

In a 100 ml, three-necked flask fitted with a magnetic stirrer,1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x58 (1.65 g, 6.6mmol) is dissolved in a 1/1 mixture of THF/H₂O (50 ml) and the solutioncontaining (2-aminophenyl)acetic acid x96 (1 g, 66 mmol) is added. ThepH is adjusted to 5 with acetic acid and the mixture is cooled to 0° C.Sodium triacetoxyborohydride (2.10 g, 10 mmol) is added and the mixtureis stirred overnight at room temperature. Water is added and the aqueousphase is extracted three times with CH₂Cl₂. The combined organic phasesare washed with brine, dried over MgSO₄ and evaporated. Purification ofthe residue by preparative chromatography on silicagel andrecrystallization from AcOEt affords 106 mg of pure1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one hydrate 173.

Yield: 8%.

LC-MS (MH⁺): 214.

Example 34 Synthesis of5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one 174

In a 50 ml, three-necked flask fitted with a magnetic stirrer, underinert atmosphere,1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x58 (0.4 g, 1.6mmol) and barium bis[(2-amino-5-chlorophenyl)acetate] x97 (0.2 g, 0.4mmol) are dissolved in a 1/1 mixture of TFA and CH₂Cl₂ (10 ml) andEt₃SiH (0.26 ml, 1.6 mmol) is added. The mixture is stirred at roomtemperature for 1 h and 3.2 mmol of Et₃SiH are added. At the end of thereaction, the mixture is diluted with water and CH₂Cl₂, extracted threetimes with CH₂Cl₂ and the combined organic phases are washed with water,dried over MgSO₄, filtered and concentrated. The residue is purified bypreparative chromatography and recrystallized from AcOEt and Et₂O toafford 9.3 mg of5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one 174.

Yield: 6%.

LC-MS (MH⁺): 248/250.

Compound 134 may be synthesized as described for compound 174.

Example 35 Synthesis of{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one33

Sodium hydride (60% wt mineral oil dispersion, 0.82 g, 1.3 eq, 20.5mmol) is washed three times by hexane (15 ml). THF (15 ml) is added atroom temperature to this clean sodium hydride, a solution of4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (3.42 g, 23 mmol, 1.4 eq) and3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x36(4.97 mg, 15.8 mmol, 1 eq) in THF (15 ml). After 3 hours of stirring atroom temperature, a small amount of sodium hydride is added in order tocomplete the reaction and stirring is pursue overnight. Water (25 ml) isthen added to the mixture and THF is removed evaporation under reducedpressure. The aqueous layer is extracted by ethyl acetate (2×50 ml), theresulting organic layer is dried over MgSO₄, filtered and concentratedto dryness. The residue is purified by preparative chromatography(benzine/AcOEt:50/50) to afford 4.33 g of{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one33.

Yield: 72%.

LC-MS (MH⁺): 381/383.

Compounds 30, 31, 32, 34 and 50 may be synthesized as described forcompound 33.

4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x103, used in the synthesis ofcompound 50, may be prepared according to the following scheme:

(i) 5-hydroxy-4-(2,2,2-trifluoroethyl)furan-2(5H)-one x100

Glyoxylic acid monohydrate (2.43 g, 26.4 mmol), morpholine hydrochloride(3.59 g, 29 mmol) and dioxane (10.5 ml) are stirred together at roomtemperature. Water (14 ml) is added and the reaction mixture is stirredfor a few minutes until it becomes homogeneous.4,4,4-trifluorobutyraldehyde x99 (3.16 g, 25.1 mmol) is added and themixture is stirred for 1 h at room temperature and under refluxconditions overnight. The mixture is diluted in tert-butylmethyletherand washed with water. The aqueous phase is re-extracted withtert-butylmethylether. The organic extracts are combined, dried overmagnesium sulphate, filtered and concentrated in vacuo to obtain5-hydroxy-4-(2,2,2-trifluoroethyl)furan-2(5H)-one x100 as a yellow oil(3.76 g, 81%). The product is used in the next reaction without furtherpurification.

(ii)1-benzyl-5-hydroxy-4-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-pyrrol-2-onex101

A solution of 5-hydroxy-4-(2,2,2-trifluoroethyl)furan-2-one x100 (3.76g, 20.4 mmol) in isopropyl alcohol (20 ml) is added to a solution ofbenzylamine (2.7 ml, 25.0 mmol) in isopropylalcohol (20 ml) withstirring at room temperature. The reaction mixture is heated at 30° C.overnight until completion. The solution containing crude1-benzyl-5-hydroxy-4-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-pyrrol-2-onex10 is used as such in the next step.

(iii) 1-benzyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x102

The crude solution of1-benzyl-5-hydroxy-4-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-pyrrol-2-onex101 in isopropyl alcohol (40 ml) is added to a suspension of Pd(C)(10%) (0.53 g) in isopropylalcohol (40 ml) and the resulting solution isdegassed 3 times with nitrogen. The reaction mixture is stirred underhydrogen (balloon) for 1 day. The Pd(C) is removed by filtration throughcelite, and the filtrates are concentrated under reduced pressure.Purification by chromatography on silicagel (petroleum ether/ethylacetate 10/50) affords 1.67 g of1-benzyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x102.

RMN ¹H(CDCl₃): 2.16 (3H, m); 2.59 (2H, m); 2.92 (1H, t; J=9.6 Hz); 3.36(1H, t, J=9.6 Hz); 4.38 (2H, dd, J=14.4 & 24 Hz); 7.17 (2H, m); 7.27(3H, m).

(iv) 4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x103

1-Benzyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x102 (1.67 g, 6.5mmol) is dissolved in diethyl ether (17 ml) and anhydrous tert-butanol(7 ml). The solution is cooled to −78° C. and ammonia (33 ml) iscondensed into the flask. Sodium (0.373 g, 16.2 mmol) is added to thesolution portionwise at −78° C., followed by the anhydrous tert-butanol(7 ml). The reaction mixture is stirred at −78° C. for 2-3 h. Ethanol(50 ml) is slowly added. The mixture is warmed to room temperature andstirred overnight. Saturated ammonium chloride is added and the mixtureis extracted with ether (3 times). The organic layers are combined,dried over magnesium sulphate, filtered and concentrated in vacuo toobtain 4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x103 as an orange solid(0.61 g).

Yield: 56%.

RMN ¹H(CDCl₃): 2.10 (1H, m); 2.21 (2H, m); 2.45 (1H, dd, J=2.4 & 8.4Hz); 2.75 (1H, m); 3.10 (1H, t; J=8.8 Hz); 3.52 (1H, t, J=8.8 Hz), 6.11(H, s broad).

Example 36 Synthesis of1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one62

36.1. Synthesis of 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine x105

A mixture of 6-chloropyridazin-3-amine x104 (24.63 g, 0.19 mol) and2-bromo-1-cyclopropylethanone (31 g, 0.190 mol, 1 eq) in dimethoxyethane(400 ml) is refluxed under inert atmosphere for 2 days. After cooling toroom temperature, the solvent is removed under reduced pressure, thecrude is taken up in water (100 ml) and extracted with ethyl acetate(2×300 ml). The cumulated organic layers are dried over MgSO₄, filteredand condensed under reduced pressure to furnish6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine x105 (Yield: 42%) whichis used as such in the next step. Note that further title compound x105can be extracted from aqueous layer after neutralization to pH 5 byaddition of sodium hydroxyde, extraction with dichloromethane, drying(MgSO₄), filtration and condensation under reduced pressure (additional11.13 g are then collected).

Overall yield: 73% (26.85 g).

LC-MS (MH⁺): 194/196.

The following compounds may be synthesized according to the same method:

x106 6-chloro-2-(4- RMN ¹H (DMSO): 2.36 methylphenyl)imidazo[1,2- (s,3H), 7.31 (d, 2H), 7.51 b]pyridazine (d, 1H), 7.92 (d, 2H), 8.27 (d,2H), 8.94 (s, 1H) x107 6-chloro-2-cyclobutylimidazo[1,2- LC-MS (MH⁺):208/210 b]pyridazine x108 2-cyclopropyl-6-fluoroimidazo[1,2- LC-MS(MH⁺): 177 a]-pyridine x109 6-chloro-2-cyclopropylimidazo[1,2- LC-MS(MH⁺): 193/195 a]-pyridine

36.2. Synthesis of6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde x110

6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine x105 (1.88 g, 9.71 mmol)and hexamethyltetramine (HMTE, 13.61 g, 97.09 mmol, 10 eq) intrifluoroacetic acid (75 ml) are heated at 60° C. during 6 days. Aftercooling and solvent evaporation under reduced pressure, the crudeproduct is dissolved in dichloromethane (150 ml). The organic layer iswashed with water (150 ml) and the resulting aqueous layer is extractedwith dichloromethane (150 ml). The cumulated organic layers are driedover MgSO₄, filtered and the solvent is removed by evaporation underreduced pressure. The resulting crude compound is purified bypreparative chromatography (benzine/AcOEt:80/20) affording 0.82 g of6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde x110.

Yield: 45%.

LC-MS (MH⁺): 222/224.

¹H NMR (CDCl₃) δ1.20 (m, 4H), 2.89 (m, 1H), 7.26 (m, 1H), 7.80 (m, 1H),10.49 (m, 1H).

The following compounds may be synthesized according to the same method:

x111 6-chloro-2-(4- LC-MS (MH⁺): methylphenyl)imidazo[1,2- 272/274b]pyridazine-3-carbaldehyde x112 6-chloro-2-cyclobutylimidazo[1,2- NMR¹H (CDCl₃) b]pyridazine-3-carbaldehyde δ 2.15 (m, 1H), 2.42- 2.51 (m,5H), 4.29 (m, 1H), 7.29 (d, 1H), 7.99 (d, 1H), 10.42 (s, 1H) x1132-cyclopropyl-6-fluoroimidazo[1,2- LC-MS (MH⁺): 205b]pyridazine-3-carbaldehyde x114 6-chloro-2-cyclopropylimidazo[1,2-LC-MS (MH⁺): 221/223 b]pyridazine-3-carbaldehyde

36.3. Synthesis of(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115

Sodium borohydride (5.62 mg, 6.62 mmol, 1.3 eq) is added dropwised, atroom temperature, to a solution of6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde x110 (958mg, 4.32 mmol) in methanol (100 ml). After 1 hour, the reaction isquenched by water (100 ml) and the crude product is extracted bydichloromethane (2×100 ml). The organic layers are dried over MgSO₄,filtered and condensed under reduced pressure to afford(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115 whichis used without any further purification.

Yield: 93%.

¹H NMR δ 0.95 (m, 4H), 2.24 (m, 1H), 4.84 (m, 2H), 5.21 (m, 1H), 7.28(d, 9.35 Hz, 1H), 8.04 (d, 9.35 Hz, 1H).

The following compounds may be synthesized according to the same method:

x116 [6-chloro-2-(4- LC-MS (MH⁺): 274/276 methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methanol x117 (6-chloro-2-cyclobutylimidazo[1,2- NMR ¹H(CDCl₃) b]pyridazin-3-yl)methanol δ 2.10 (m, 1H), 2.34- 2.56 (m, 5H),3.81 (m, 1H), 4.99 (m, 1H), 7.04 (d, 1H), 7.86 (d, 1H) x118(2-cyclopropyl-6-fluoroimidazo[1,2- LC-MS (MH⁺): 207a]pyridin-3-yl)methanol x119 (2-cyclopropyl-6-chloroimidazo[1,2- LC-MS(MH⁺): 223/225 a]pyridin-3-yl)methanol

36.4. Synthesis of1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one62

A solution of(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115 (889mg, 3.97 mmol), 4-(2,2-difluorovinyl)pyrrolidin-2-one (643 mg, 4.37mmol, 1.1 eq) and paratoluenesulfonic acid (76 mg, 0.40 mmol, 0.1 eq) intoluene (20 ml) is heated under reflux for 16 h. After cooling, thesolvent is removed under reduced pressure, the crude product isdissolved in dichloromethane (100 ml). The organic layer is washed bywater (150 ml). The aqueous layer is extracted by dichloromethane (100ml). The cumulated organic layers are dried over MgSO₄, filtered andevaporated under reduced pressure. The residue is purified bypreparative chromatography over silicagel (benzine/AcOEt:60/40) toafford1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one62 after recrystallization in diisopropylether.

Yield: 28%.

LC-MS (MH⁺): 353/355.

Compounds 18, 19, 51, 52, 71 and 72 may be prepared as described forcompound 62.

Example 37 Synthesis of1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one65

A solution of1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one62 (340 mg, 0.964 mmol), sodium terbutoxide (11.2 mg, 1.16 mmol, 1.2eq), palladium (II) acetate (21.6 mg, 0.093 mmol, 0.1 eq) and BINAP (120mg, 0.193 mmol, 0.2 eq) in toluene (20 ml) is heated during 1.5 h underreflux. After cooling to room temperature, the crude reaction mixture isfiltered. The organic layer is washed with water (2×30 ml) and driedover MgSO₄. The solvent is evaporated under reduced pressure and thecrude product is purified by preparative chromatography(CH₂Cl₂/MeOH/NH₄OH: 97/3/0.3 (v/v/v)).1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one65 is obtained after recrystallization in dichloromethane/hexane.

Yield: 55%.

LC-MS (MH⁺): 376.

Compounds 66, 67, 68 and 70 may be prepared as described for compound65.

Example 38 Synthesis of4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one42

A solution of{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one33 (500 mg, 1.31 mmol, 1 eq) and sodium methoxide (142 mg, 2.63 mmol, 2eq) in methanol (5 ml) is heated in microwave apparatus (300 W, T 150°C.) until complete conversion (0.5 h). After cooling to roomtemperature, water (10 ml) is added and the methanol is removed underreduced pressure. Subsequent extraction with dichloromethane (2×20 ml),drying of cumulated organic layers over MgSO₄, filtration and solventevaporation under reduced pressure affords the crude reaction mixturewhich is recristallized in AcOEt/iPr₂O to yield 0.46 g of4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one42.

Yield: 93%.

LC-MS (MH⁺): 377.

Compounds 36, 38, 39, 58, 60, 75, 76, 77, 78, 79, 80 and 81 may beprepared as described for compound 42.

Example 39 Synthesis of1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one73

A solution of1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one33 (200 mg, 0.48 mmol, 1 eq) and n-butylamine (0.14 g, 0.96 mmol, 2 eq)in acetonitrile (2 ml) is heated in microwave apparatus (300 W, Tmax150° C.) until complete conversion (2 h). After cooling to roomtemperature, a potassium carbonate aqueous saturated solution (10 ml) isadded and the crude reaction mixture is extracted with dichloromethane(3×20 ml). Subsequent drying of cumulated organic layers over MgSO₄,filtration and solvent evaporation under reduced pressure furnished thecrude reaction mixture which is purified by preparative chromatographyover silicagel (CH₂Cl₂/MeOH/NH₄OH: 95/5/0.5) to afford1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one73.

Yield: 80%.

LC-MS (MH⁺): 418.

Compounds 41, 44, 54, 55, 57, 59, 61, 63 and 74 may be prepared asdescribed for compound 73.

Example 40 Synthesis of1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one46

A mixture of1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one30 (400 mg, 1.11 mmol) and sodium methanethiolate (155 mg, 2.22 mmol,2.2 eq) in THF is heated in a microwave apparatus (300 W, Tmax 150° C.)during 15 minutes. After cooling to room temperature, hydrolysis (15 mlof water), extraction (ethyl acetate, 3×15 ml), the cumulated organiclayers are dried over MgSO₄, filtered and condensed under reducepressure to afford an oil which is purified under preparativechromatography over silicagel (Gradient: CH₂Cl₂ to CH₂Cl₂/MeOH/NH₄OH99/1/0.1 (v/v/v)). Recrystallization in diisopropyl ether affords1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one46.

Yield: 26%.

LC-MS (MH⁺): 373.

Example 41 Synthesis of1-[{6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one48

To1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one46 (100 mg, 0.27 mmol) in chloroform (5 ml) is added 4-chloroperbenzoicacid (93 mg, 0.54 mmol, 2 eq) at −30° C. After 15 minutes, the mixtureis warmed to room temperature then stirred for additional 16 hours. Thenis added further 4-chloroperbenzoic acid (46 mg, 0.27 mmol, 1 eq) andstirring is pursued during additional 16 h. The organic layer is washedwith a saturated aqueous Na₂CO₃ solution (3 ml), then with a saturatedaqueous Na₂S₂O₅ solution (3 ml). After drying over MgSO₄ and filtration,the organic layer is condensed under reduced pressure. The resultingcrude product is purified by chromatography (CH₂Cl₂/MeOH/NH₄OH 99/1/0.1)to yield1-{[6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one48.

Yield: 55%.

LC-MS (MH⁺): 405.

Example 42 Synthesis of1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one49

4-chloroperbenzoic acid (36 mg, 0.134 mmol, 1 eq) is added to a solutionof1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one33 (50 mg, 0.134 mmol) in chloroform (2 ml) at −30° C. After 30 minutes,the mixture is warmed to room temperature then stirred for additional 16hours. After hydrolysis with a saturated aqueous NaHCO₃ solution (2 ml)and extraction with CHCl₃ (2 ml), the cumulated organic layers are driedover MgSO₄ and condensed under reduced pressure. The resulting crudeproduct is purified by reverse phase liquid chromatography (gradientacetonitrile/water/TFA) to yield1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one82.

Yield: 38%.

LC-MS (MH⁺): 389.

Example 43 Synthesis of3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carbonitrile82

A solution of1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one33 (1 g, 2.63 mmol), nickel (II) bromide (579 mg, 2.63 mmol, 1 eq) andsodium cyanide (257 mg, 5.25 mmol, 2 eq) in N-methylpyrrolidin-2-one (15ml) is heated at 200° C. in microwave apparatus for 30 minutes. Aftercooling to room temperature, ethyl ether (100 ml) is added, and theresulting solution is washed three time by 50 ml of water. The resultingorganic layer is dried over magnesium sulfate, filtrated and condensedunder reduced pressure. The resulting crude oil is purified bypreparative chromatography over silicagel (CH₂Cl₂/MeOH/NH₄OH: 99/1/0.1),then recristallized in ethyl acetate and diisopropyl ether to afford3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carbonitrile82.

Yield: 23%.

LC-MS (MH⁺): 372.

Example 44 Synthesis of4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one84

A solution of sodium carbonate (28 mg, 0.26 mmol, 2 eq in 0.25 ml ofwater) is added to a solution of1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one33 (50 mg, 0.13 mmol), phenylboronic acid (18 mg, 0.144 mmol, 1.1 eq)and tetrakis(triphenylphosphine) palladium (8 mg, 0.007 mol, 0.05 eq) indimethoxyethane (2 ml) at 75° C. The reaction mixture is stirredovernight. The reaction mixture is filtered, condensed under reducedpressure, the residue is taken in 2 ml of water and extracted with ethylacetate (2×2 ml). The cumulated organic layers are dried over MgSO₄,filtered and condensed under reduced pressure to afford the crudeproduct which is purified by preparative chromatography(CH₂Cl₂/MeOH/NH₄OH: 99/1/0.1 (v/v/v)) yielding the4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one84.

Yield: 58%.

LC-MS (MH⁺): 423.

Compounds 83, 85 and 86 may be prepared as described for compound 84.

Example 45 Synthesis of1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one40

Freshly prepared cyclopropyl magnesium bromide (as described in J. Am.Chem. Soc. (2002), 124, 13856-63; with cyclopropylbromide (48 mg, 0.4mmol, 1.2 eq) and magnesium powder (10 mg) in 5 ml of THF) is addedslowly and dropwise to a mixture of1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one30 (120 mg, 0.33 mmol) and iron (III) acetylacetone (3 mg, 0.0165 mmol,0.05 eq) in THF (5 ml) at room temperature. The reaction is kept at roomtemperature for 16 h, then hydrolyzed (10 ml of 1 N HCl), neutralizedwith a saturated solution of NaHCO₃ until alkaline pH. The crude productis extracted with ethyl acetate (3×20 ml). The cumulated organic layersare dried over MgSO₄, filtered and condensed under reduced pressure. Theresidue is purified by preparative chromatography (CH₂Cl₂/MeOH/NH₄OH:98/210.2 (v/v/v)) to afford1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one40.

Yield 25%

LC-MS (MH⁺): 367.

Example 46 Synthesis of1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one202

46.1. Synthesis 6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x122.

To a solution of 3-phenyl-1H-pyrazol-5-amine x120 (31.4 mmol, 1 eq, 5 g)in AcOH (30 ml) is added 1,1,3,3-tetraethoxy-2-methylpropane x121 (31.4mmol, 1 eq, 7.36 g). The mixture is heated at 100° C. during 4 hours.After evaporation of the solvent under reduced pressure, the crudeproduct is poured in saturated NaHCO₃ aqueous solution and thenextracted with AcOEt. The cumulated organic layers are dried over MgSO₄,filtered and evaporated under reduce pressure. The crude mixture isrecristallized in AcOEt to afford6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x122 as a solid (3 g).

Yield: 45%.

LC-MS (MH⁺): 210.

The following compounds may be synthesized according to the same method:

x123 2-(2-thienyl)pyrazolo[1,5-a]pyrimidine LC-MS (MH+): 202 x1242-phenylpyrazolo[1,5-a]pyrimidine LC-MS (MH⁺): 196 x1252-(2-furyl)pyrazolo[1,5-a]pyrimidine LC-MS (MH⁺): 186 x1262-(4-bromophenyl)pyrazolo[1,5- LC-MS (MH⁺): 274/276 a]pyrimidine x1272-(4-fluorophenyl)pyrazolo[1,5- LC-MS (MH⁺): 214 a]pyrimidine x1282-(4-chlorophenyl)-6- LC-MS (MH⁺): 244/246methylpyrazolo[1,5-a]pyrimidine x129 2-(4-chlorophenyl)pyrazolo[1,5-LC-MS (MH⁺): 230/232 a]pyrimidine x130 6-chloro-2-(4- LC-MS (MH⁺):264/266/ chlorophenyl)pyrazolo[1,5-a]pyrimidine 268

46.2. Synthesis of1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one202

To a solution of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (3.18mmol, 1 eq, 0.5 g) in toluene (20 ml) is added thionyl chloride (3.5mmol, 1.1 eq, 0.416 g). The mixture is stirred vigorously overnight at80° C. After this time, 6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x122(3.18 mmol, 1 eq, 0.665 g) and AlCl₃ (3.18 mmol, 1 eq, 0.424 g) aresuccessively added. The mixture is stirred at 80° C. for 2 hours. Afterevaporation of the solvent under reduced pressure, the crude mixture ispoured to water and extracted with dichloromethane. The cumulatedorganic layers are dried over MgSO₄, filtered over celite and evaporatedunder reduced pressure. The crude reaction mixture is purified bychromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH 98/2/0.2 (v/v/v)) andcrystallized with AcOEt to afford 0.5 g of1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one202.

Yield: 50%.

LC-MS (MH⁺): 349.

Compounds 205 and 210 may be prepared as described for compound 202.

Example 47 Synthesis of4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one207

47.1. Synthesis of6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol x133

To a solution of 3-phenyl-1H-pyrazol-5-amine x131 (52 mmol, 1 eq, 8.3 g)in 50 ml of AcOH, is added ethyl 2-fluoro-3-oxobutanoate x132 (57 mmol,1.2 eq, 8.5 g). The mixture is heated at 100° C. for 0.5 hour. Aftercooling to room temperature, the resulting product is filtered, washedwith EtOH and dried to afford 8.1 g of6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol x133.

Yield: 55%

LC-MS (MH⁺): 244.

The following compounds may be synthesized according to the same method:

x134 5,6-dimethyl-2-phenylpyrazolo[1,5- LC-MS (MH⁺): 240a]pyrimidin-7-ol x135 2-cyclopropyl-5-methylpyrazolo[1,5- LC-MS (MH⁺):190 a]pyrimidin-7-ol

47.2. Synthesis of7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x136.

A solution of 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-olx133 (25 mmol, 1 eq, 6.2 g) in POCl₃ (150 ml) is heated at 125° C.overnight. After cooling to room temperature, the solution is diluted indichloromethane and quenched on ice (temperature must be kept under 25°C.). After separation of the organic layer, the aqueous phase isextracted twice with dichloromethane. The cumulated organic-layers aredried over MgSO₄, filtered, evaporated under reduced pressure and theresidue purified by chromatography on silicagel (CH₂Cl₂) to afford 6.6 gof 7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x136.

Yield: 89%.

LC-MS (MH⁺): 262/264.

The following compounds may be synthesized according to the same method:

x137 7-chloro-5,6-dimethyl-2- LC-MS (MH⁺): 258/260phenylpyrazolo[1,5-a]pyrimidine x138 7-chloro-2-cyclopropyl-5- LC-MS(MH⁺): 208/210 methylpyrazolo[1,5-a]pyrimidine

47.3. Synthesis 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidinex139.

To a solution of7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x136 (22.9mmol, 1 eq, 6 g) in 150 ml of AcOH at 0° C., is added zinc dust (68mmol, 3 eq, 4.5 g). The mixture is stirred at 25° C. overnight. Afterevaporation of the solvent under reduced pressure, the crude product ispoured on ice and quenched with a saturated aqueous NaHCO₃ solution andextracted with AcOEt. The cumulated organic layers are washed withbrine, dried over MgSO₄, filtered and evaporated under reduced pressureto yield 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x139.

Yield: 90%.

LC-MS (MH⁺): 228.

The following compounds may be synthesized according to the same method:

x140 5,6-dimethyl-2-phenylpyrazolo[1,5- LC-MS (MH⁺): 224 a]pyrimidinex141 2-cyclopropyl-5-methylpyrazolo[1,5- LC-MS (MH⁺): 174 a]pyrimidine

47.4. Synthesis of4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one207

4-(2,2-difluorovinyl)-1-(hydroxymethyl)pyrrolidin-2-one x142 is preparedas described in example 1.1 from 4-(2,2-difluorovinyl)pyrrolidin-2-onex98.

To a solution of 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidinex139 (5.6 mmol, 1 eq, 1.28 g) in 60 ml of toluene is added successively1-(hydroxymethyl)-4-propylpyrrolidin-2-one (5.6 mmol, 1 eq, 1 g) andparatoluene sulfonic acid (0.56 mmol, 0.1 eq, 0.107 g). The mixture isstirred vigorously overnight at 100° C. The solvent is removed underreduce pressure. The residue is poured in water and extracted withtoluene. The cumulated organic layers are dried over MgSO₄, filtered andevaporated under reduced pressure. The crude product purified bychromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH 98/2/0.2) to afford 237mg of4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one207 as a solid.

Yield: 11%.

LC-MS (MH⁺): 387.

Compounds 186, 188, 190, 198, 200, 206, 209, 210, 214, 215, 216, 217 and218 may be prepared as described for compound 207.

Example 48 Synthesis of1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one191

To a solution of 2-phenylpyrazolo[1,5-a]pyrimidine x124 (25.6 mmol, 1eq, 5 g) in trifluoroacetic acid (150 ml) is added1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (38.4 mmol, 1.5 eq, 6 g).The resulting solution is stirred at room temperature for three days.The solvent is removed under reduce pressure, ice is added and themixture is alkalinized by solid NaHCO₃. The mixture is extracted byAcOEt, the organic layers are washed with brine and dried over Na₂SO₄.The solvent is removed under reduce pressure and the crude reactionmixture purified by chromatography on silicagel (AcOEt/hexane 40/60).After crystallisation in AcOEt/hexane, to afford 2.06 g of1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one191 are obtained.

Yield: 24%.

LC-MS (MH⁺): 335.

Compounds 21, 25, 26, 27, 203, 243 and 245 may be prepared as describedfor compound 191.

Example 49 Synthesis of4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one211

49.1. Synthesis of(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol x143.

To a solution of6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x26 (3.37mmol, 1 eq, 0.8 g) in MeOH (20 ml) maintained at 0° C. is added sodiumborohydride (3.7 mmol, 1.1 eq, 0.14 g) and the resulting solution isstirred at room temperature during 0.5 hour. After this time, thesolvent is removed under reduced pressure. The solid residue is washedwith water, filtered and dried (under vacuum) to give 0.58 g of pure(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol x143.

Yield: 72%.

LC-MS (MH⁺): 240.

The following compounds may be synthesized according to the same method:

x144 (5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin- LC-MS (MH⁺): 2403-yl)methanol x145 [2-(2-thienyl)pyrazolo[1,5-a]pyrimidin-3- LC-MS(MH⁺): 232 yl]methanol

49.2. Synthesis of4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one211

To a solution of(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol x143 (2.4 mmol,1 eq, 0.58 g) in toluene (20 ml) is added thionyl chloride (4.8 mmol, 2eq, 353 μ□l). The mixture is heated at 80° C. for 2 hours. The resultingmixture is cooled down to room temperature and the solvent removed underreduced pressure to afford3-(chloromethyl)-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x146, towhich 5 ml of dry DMF are added.

3-(chloromethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x147 and3-(chloromethyl)-2-(2-thienyl)pyrazolo[1,5-a]pyrimidine x148 may besynthesized according to the same method

The above mentioned solution of intermediate x146 is added to a solutioncontaining 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.64 mmol, 1.1 eq,0.356 g), 6 ml of dry DMF and sodium hydride (60% dispersion in oil,2.64 mmol, 1.1 eq, 0.1 g) that have been stirred at room temperature for0.5 hour. The resulting mixture is heated up at 80° C. for 1 hour. Themixture is poured in water and extracted with AcOEt. The cumulatedorganic layers are washed with brine, dried over MgSO₄, filtered andevaporated under reduced pressure. The residue is crystallized in AcOEtto afford 0.443 g of4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one211.

Yield: 50%.

LC-MS (MH⁺): 369.

Compounds 212 and 213 may be prepared as described for compound 211.

Example 50 Synthesis of1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one192

To a solution of1-[(6-bromo-2-tertbutylpyrazolo(1,5-a)pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one190 (0.56 mmol, 1 eq, 0.2 g) in 5 ml of DME is added successivelypalladium-tetrakis-triphenylphosphine (0.019 mmol, 0.03 eq, 22 mg),cyclopropyl-boronic acid (0.727 mmol, 1.1 eq, 62 mg), and K₃PO₄ (1.98mmol, 3 eq, 0.42 g) dissolved in 4 ml of water. The mixture is degassedand stirred vigorously at 90° C. for 4 hours. The solvent is removedunder reduce pressure, water is added and the resulting mixture isextracted with dichloromethane. The organic phases are combined, washedwith brine and dried over MgSO₄. Volatiles are removed under reducepressure. The crude product is purified by chromatography on silicagel(CH₂Cl₂/MeOH/NH₄OH: 99/1/0.1) to afford 58 mg of pure1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one192 the compound in pure form.

Yield: 25%.

LC-MS (MH⁺): 355.

Compounds 194, 195, 196 and 197 may be prepared as described forcompound 192.

Example 51 Synthesis of1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one199

To a solution of1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one184 (0.66 mmol, 1 eq, 0.26 g) in 2 ml of water and 2 ml of isopropylalcohol are added successively palladium on activated carbon (10%, 0.284mmol, 0.5 eq, 30 mg), phenyl acetylene (0.68 mmol, 1.2 eq, 70 mg), andK₃PO₄ (1.13 mmol, 2 eq, 0.24 g) dissolved in 2 ml of water. The mixtureis degassed and stirred vigorously overnight at 100° C. The solvent isremoved under reduce pressure. The crude product is purified bychromatography on silicagel (AcOEt/hexane: 4/6) to afford 25 mg of1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one199.

Yield: 11%.

LC-MS (MH⁺): 373.

Example 52 Synthesis of1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one204

52.1. Synthesis of1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-onex149

To a solution of1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one186 (24 mmol, 1 eq, 10 g) in 100 ml of water are added successivelypalladium on activated carbon (10%, 1.2 mmol, 0.05 eq, 1.2 g) and K₃PO₄(48 mmol, 2 eq, 10.25 g). The mixture is degassed and stirred vigorouslyat 130° C. for 8 hours. After cooling to room temperature, the reactionmixture is filtered on celite and a 5 N hydrochloric acid solution (10ml) is added (until pH 7). The water is removed under reduce pressureand the crude is triturated with hot THF. After filtration andevaporation of THF,1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-onex149 is obtained (1.9 g).

Yield: 22%.

LC-MS (MH⁺): 351.

Compound 201 may be prepared according to the same method.

52.2. Synthesis of1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one204

To a solution of1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-onex149 (1.71 mmol, 1 eq, 0.6 g) in acetone (100 ml) is added iodomethane(17.1 mmol, 10 eq, 1.065 ml) and K₂CO₃ (17.1 mmol, 10 eq, 2.36 g). Themixture is refluxed for 5 minutes. Solvent is evaporated under reducedpressure. The crude product is purified by chromatography on silicagel(AcOEt/hexane: 1/1) and recrystallized in AcOEt to afford 0.19 g of1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one204.

Yield: 30%.

LC-MS (MH⁺): 365.

Example 53 Synthesis of1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one208

To a solution of1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one205 (0.575 mmol, 1 eq, 0.22 g) in MeOH (10 ml) is added sodium methoxide(5.75 mmol, 10 eq, 0.4 g). The mixture is heated at 80° C. for 2 hours.The solvent is removed under reduce pressure, water is added and theresulting mixture is extracted with CH₂Cl₂. The organic phases arecombined, and dried over MgSO₄. Volatiles are removed under reducedpressure to afford 89 mg of1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one208.

Yield: 33%.

LC-MS (MH⁺): 289.

Example 54 Synthesis of1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one292 and1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one290

54.1. Synthesis of 5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridine x151.

5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridine x151 is synthesizedaccording to the method described in example 20.1 using3-phenyl-1H-pyrazol-5-amine x150 and bromomalonaldehyde x9.

Yield: 13%.

LC-MS (MH⁺): 274/276.

54.2. Synthesis of1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one292 and1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one290

To a solution of 5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridine x151 (14.6mmol, 1 eq, 4 g) dissolved in TFA (100 ml) is added1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (21.8 mmol, 1.5 eq, 3.44g). The mixture is heated at 100° C. for 2 hours. After evaporation ofthe solvent under reduced pressure, the crude reaction mixture is pouredon ice and a saturated NaHCO₃ aqueous solution is added until pH 7. Themixture is extracted with CH₂Cl₂. The cumulated organic layers are driedover MgSO₄, filtered and evaporated under reduced. The products arepurified by chromatography on silicagel (Hexane/AcOEt 6/4).

Yield: 50% for compound 292 and 21% for compound 290.

LC-MS (MH⁺): 413/415 for these two compounds.

Example 55 Synthesis of1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one221

55.1. Synthesis of 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine x153.

5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine x153 is synthesizedaccording to the method described in example 20.1 using3-methyl-1H-pyrazol-5-amine b40 and bromomalonaldehyde a9.

Yield: 10%.

LC-MS (MH⁺): 212/214.

55.2. Synthesis of tert-butyl5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x154

To a solution of 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine x153 (13.4mmol, 1 eq, 2.86 g) in acetonitrile (10 ml) is addeddi(tert-butyl)dicarbonate (13.4 mmol, 1 eq, 2.94 g) and N,N-dimethylaminopyridine (DMAP) (13.4 mmol, 1 eq, 1.64 g). The resulting mixture isrefluxed during 1 minute. After cooling to room temperature, the solventis evaporated under reduce pressure, and the residue washed with water,filtered and dried under vacuum to afford 3.62 g of tert-butyl5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x154 as asolid.

Yield: 86%.

LC-MS (MH⁺): 312/314.

55.3. Synthesis of tert-butyl5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155

A mixture of tert-butyl5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x154 (10.8mmol, 1 eq, 3.37 g), N-bromosuccinimide (1.92 g, 1 eq, 10.8 mmol) andazo-bisiso-butyronitrile (AIBN) (10.8 mmol, 1 eq, 1.77 g) in CCl₄ (50ml) is heated for 2 hours at 80° C. The solvent is removed under reducepressure, water is added and the resulting mixture is extracted withdichloromethane. The combined organic phases are dried over MgSO₄,filtered and volatiles removed under reduced pressure. The product ispurified by chromatography on silicagel (hexane/AcOEt 8/2) andrecristallized in AcOEt to afford 0.28 g of pure tert-butyl5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155.

Yield: 6.6%.

LC-MS (MH⁺): 390/392/394.

55.4. Synthesis of1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one221

To a solution of 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.86 mmol, 2eq, 0.42 g) in dry DMF (5 ml) maintained at 0° C. is added natriumhydride (60% dispersion in oil; 2.86 mmol, 2 eq, 0.114 g). The resultingmixture is stirred at room temperature for 0.5 hour and tert-butyl5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155(1.43 mmol, 1 eq, 0.56 g) dissolved in DMF (2 ml) is added. Theresulting mixture is stirred overnight at room temperature. The mixtureis poured in water and extracted with AcOEt. The cumulated organiclayers are dried over MgSO₄, filtered and evaporated under reducedpressure. The crude mixture is purified twice by chromatography onsilicagel (CH₂Cl₂/MeOH/NH₄OH 98/2/0.2) to afford pure1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one221 (0.025 g).

Yield: 4.9%.

LC-MS (MH⁺): 357/359.

Example 56 Synthesis of1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one235

To a solution of 6-bromo-1H-pyrrolo[2,3-b]pyridine x156 (2.5 mmol, 1.06eq, 0.49 g) in 15 ml of toluene is added successively1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (2.35 mmol, 1 eq, 0.37 g)and paratoluene sulfonic acid (1.25 mmol, 0.5 eq, 0.24 g). The mixtureis stirred at reflux for 1 hour. The reaction mixture is quenched with asaturated NaHCO₃ aqueous solution and then extracted with AcOEt. Thecombined organic layers are dried over MgSO₄, filtered and evaporatedunder reduced pressure. The crude product is purified by chromatographyon silicagel (CH₂Cl₂/MeOH/NH₄OH 95/510.5), then by chromatography on areverse phase (Sunfire Prep MS C18 ODB column (5 μm, 19×50 mm); eluent:gradient of water/acetonitrile/TFA; 25° C.) to afford 224 mg of1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one235 as a solid.

Yield: 28%.

LC-MS (MH⁺): 336/338.

Compounds 236, 237, 238 and 239 may be prepared as described forcompound 235.

Example 57 Synthesis of1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one239

To 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one 231(100 mg, 1 eq, 0.39 mmol) dissolved in 1,2-dimethoxyethane (3 ml) isadded m-chloroperoxybenzoic acid (111 mg, 1.6 eq, 0.64 mmol). Theresulting solution is stirred at room temperature for 20 hours. Hexane(10 ml) is added to the reaction mixture, and the decanted syrup iswashed twice with hexane by decantation and dried under vacuum. To theresidual solid are added 3 ml of water and a saturated solution of K₂CO₃until pH 9. The resulting mixture is extracted with CH₂Cl₂ and theorganic phase is dried over MgSO₄. Volatiles are removed under reducedpressure and the residue is purified twice by chromatography onsilicagel (CH₂Cl₂/MeOH/NH₄OH 95/5/05) to give 50 mg of1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one239.

Yield: 47%.

LC-MS (MH⁺): 274.

Example 58 Synthesis of1-[(5-fluoro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one 278

To a solution of 5-fluoroindole x157 (405 mg, 3 mmol, 1 eq) of in DMF (7ml) maintained under argon is added NaH (60% in mineral oil; 120 mg, 3mmol, 1 eq). The resulting mixture is stirred for three hours at roomtemperature, then a solution of1-(chloromethyl)-4-propylpyrrolidin-2-one x63 in DMF (1 M, 3 ml, 3 mmol,1 eq) is added. The reaction mixture is stirred for 20 hours at roomtemperature. Water (70 ml) is added and the resulting mixture isextracted with ethyl acetate (30 ml). The organic phase is washed twicewith water and dried over Na₂SO₄. After filtration and evaporation ofvolatiles, the crude product is purified by two consecutivechromatographies on silicagel (CH₂Cl₂/MeOH gradient, then CH₂Cl₂). Pure1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one278 is obtained as syrup (274 mg).

Yield: 33%.

LC-MS (MH⁺): 275.

Compounds 275, 276, 277, 279, 280, 281 and 282 may be synthesized asdescribed for compound 278.

Example 59 Synthesis of1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one 295

To a solution of 1,2,3,4-tetrahydroquinoline x158 (400 mg, 3 mmol, 1 eq)in DMF (7 ml) maintained under argon is added NaH (60% in mineral oil;120 mg, 3 mmol, 1 eq). The reaction mixture is stirred for three hour atroom temperature, then a solution of1-(chloromethyl)-4-propylpyrrolidin-2-one x63 in DMF (1 M, 3 ml, 3 mmol,1 eq) is added. The reaction mixture is stirred for 20 hours at the sametemperature. Water (70 ml) is added and the resulting mixture isextracted with ethyl acetate (30 ml). The organic phase is washed twicewith water and dried over Na₂SO₄. After filtration and evaporation, thecrude product is purified by two consecutive chromatographies onsilicagel (CH₂Cl₂/MeOH gradient, then CH₂Cl₂). Pure1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one 295 isobtained as syrup (231 mg).

Yield: 28%.

LC-MS (MH⁺): 273.

Example 60 Synthesis of1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one 274

60.1. Synthesis of 2-chloro-1H-indole x160.

At room temperature, POCl₃ (1 ml, 10.82 mmol, 2 eq) is added to a wellstirred suspension of N,N-diethylaniline (1 ml, 5.41 mmol, 1 eq) and1,3-dihydro-2H-indol-2-one x159 (0.72 g, 5.41 mmol, 1 eq) in dry toluene(15 ml). The mixture is heated at reflux during 3 hours. After cooling,water (15 ml) is carefully added and the organic layer is washed withwater (3×25 ml). The organic layer is dried on anhydrous MgSO₄, filteredoff and concentrated under reduced pressure to obtain 0.76 g of2-chloro-1H-indole x160 as an orange solid (0.76 g, 93%).

Yield: 93%.

LC-MS (MH⁻): 150/152.

Due to relative unstability of the product, it is directly used in thefollowing step.

1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one x161 (LC-MS (MH⁺): 153/155)and 2,5-dichloro-1H-indole x162 (¹H NMR (CDCl₃): δ 6.37 (s, 1H);7.12-7.24 (m, 2H overlapped with solvent), 7.49 (s, 1H), 8.10 (s broad,1H)) may be synthesized according to the same method.

60.2. Synthesis of1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one 274

At −78° C., NaH (60% in mineral oil; 220 mg, 5.52 mmol, 1.1 eq) is addedto a solution of 2-chloro-1H-indole x160 (0.76 g, 5.02 mmol, 1 eq) indry DMF (50 ml). The temperature is raised to −20° C. during 20 minutes,then 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.76 g, 5.02 mmol, 1eq) dissolved in DMF (10 ml) is added drop wise. After 2 hours at roomtemperature, water (50 ml) is added. The aqueous layer is extracted withCH₂Cl₂ (3×30 ml). The combined organic layers are dried on anhydrousMgSO₄, filtered off and concentrated under reduced pressure to obtain aliquid that is purified on silicagel (AcOEt/Benzine 1/9) yielding1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one 274 as acolorless liquid (605 mg).

Yield: 42%.

LC-MS (MH⁺): 291/293.

Compounds 293, 294, 296, 322, 323 and 324 may be synthesized accordingto the same method.

Example 61 Synthesis of1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propyl-pyrrolidin-2-one 300

A solution of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (0.472 g, 1eq, 3 mmol), (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6(38.5 mg, 5 mol %, 0.15 mmol) and 2-chloro-1H-benzimidazole x163 (1.2eq, 3.3 mmol, 0.504 g) in acetonitrile (3 ml) is irradiated in amicrowave apparatus (CEM discover) during 0.75 h (100 w). After cooling,evaporation of the solvent under reduce pressure and purification bypreparative chromatography on reverse phase,1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propyl-pyrrolidin-2-one 300is isolated as a clear oil (0.42 g).

Yield: 49.2%.

LC-MS (MH⁺): 292/294.

Compounds 301, 304, 310 and 319 may be synthesized according to the samemethod.

Example 62 Synthesis of1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one305 and1-[(2-chloro-5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one306

A mixture of the two compounds is synthesized according to the proceduredescribed in example 61 using 2-chloro-5-methoxy-1H-benzimidazole x164and 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2. Compounds areseparated by preparative chiral chromatography (EtOH/heptane: 10/90, 30°C., 300 ml/min).

Yield: 27% for compound 305 and 18% for compound 306.

LC-MS (MH⁺): 322/324.

Compounds 302, 303, 307, 308, 309, 311, 312, 313, 314, 315, 316, 317 and318 may be synthesized according to the same method.

Example 63 Synthesis of1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one320

Under argon, BBr₃ (1 M in CH₂Cl₂) (1.86 ml, 1.8645 mmol, 2 eq) is addeddrop wise to a solution of1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one305 (0.3 g, 0.9322 mmol, 1 eq) in dry CH₂Cl₂ (20 ml). After 48 hours atroom temperature, saturated aqueous solution of NaHCO₃ (20 ml) is added.The aqueous layer is extracted with CH₂Cl₂ (3×20 ml) then the combinedorganic layers are dried on anhydrous MgSO₄, filtered off and evaporatedunder reduced pressure. The remaining pale yellow solid isrecrystallized in MeCN/H₂O (9/1) to yield 102 mg of1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one320 as a white solid.

Yield: 35%.

LC-MS (MH⁺): 308/310.

Compound 321 may be synthesized according to the same method.

Example 64 Synthesis of1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one285

64.1. Synthesis of1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one x166

A mixture of 6-chloro-1H-purine x165 (2 g, 12.93 mmol, 1 eq),1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (2.44 g, 15.53 mmol, 1.2eq) and N,N-diethylcarbamoylchloride (332 mg, 1.293 mmol, 0.1 eq) inMeCN (30 ml) is heated at 100° C. in microwave apparatus during 5 hours.After cooling, the solvent is evaporated and the crude is purified onsilicagel (CH₂Cl₂/MeOH (+NH₄OH 10%) 95/5) to yield 3.8 g of1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one x166 as apale yellow solid.

Yield: 99%.

¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, 7.18 Hz, 3H), 1.33 (m, 4H), 2.07 (dd,17.12, 8.18 Hz, 1H), 2.36 (m, 1H), 2.53 (dd, 17.12, 8.56 Hz, 1H), 3.15(dd, 9.32, 7.05 Hz, 1H), 3.68 (dd, 9.32, 8.06 Hz, 1H), 5.70 (m, 2H),8.37 (s, 1H), 8.78 (s, 1H).

64.2. Synthesis of1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one285

A mixture of 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-onex166 (250 mg, 0.85 mmol, 1 eq) and cyclopropylamine (1 ml) is heated at50° C. during 24 hours in THF. After cooling, a saturated aqueoussolution of NaHCO₃ is added and the aqueous phase is extracted withAcOEt. The combined organic layers are dried on anhydrous MgSO₄,filtered of and evaporated under reduced pressure. The crude mixture ispurified by preparative HPLC to yield1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one285.

Yield: 54%.

LC-MS (MH⁺): 315.

Compounds 286, 287, 288 and 289 may be synthesized according to the samemethod.

Example 65 Synthesis of1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one272

65.1. Synthesis of 6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine x168.

A solution of cyclopropanecarbaldehyde (0.89 g, 12.76 mmol, 1.2 eq),5-bromopyridine-2,3-diamine x167 (2 g, 10.63 mmol, 1 eq) in AcOH (20 ml)and 1,4-dioxane (40 ml) is heated at 110° C. during 24 hours. Aftercooling, the solvents are evaporated under reduced pressure. Theresulting brown solid is recrystallized in CH₂Cl₂/hexane (1/1) to yield0.53 g of 6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine x168 as anorange solid.

Yield: 21%.

LC-MS (MH⁺): 238/240.

6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridine x169 may be synthesizedaccording to the same method (LC-MS (MH⁺): 274/276).

65.2. Synthesis of1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one272

1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one272 is synthesized according to the procedure described in example 61using 6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine x168 and4-(2,2-difluorovinyl)-1-(hydroxymethyl)pyrrolidin-2-one x142.

Yield: 25%.

LC-MS (MH⁺): 238/240.

Compounds 266, 267, 269, 270 and 271 may be synthesized according to thesame method.

Example 66 Synthesis of1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one93

66.1. Synthesis of (5-chloro-2-imino-1,3-thiazol-3(2H)-yl)acetic acidhydrobromide x171.

At room temperature, 5-chloro-1,3-thiazol-2-amine x170 (1.49 g, 11.03mmol, 1 eq) is added to a well stirred solution of bromoacetic acid(1.68 g, 11.03 mmol, 1 eq) in EtOH (50 ml). The mixture is heated atreflux during 8 hours. After cooling, the resulting precipitate isfiltrated dried under vacuum to yield 288 mg of(5-chloro-2-imino-1,3-thiazol-3(2H)-yl)acetic acid hydrobromide x171 asa white solid.

Yield: 10%.

LC-MS (MH⁺): 193/195

66.2. Synthesis of 2,6-dichloroimidazo[2,1-b][1,3]thiazole x172

POCl₃ (0.5 ml, 5.27 mol, 5 eq) is added to a suspension of acid x171(0.288 g, 1.05 mol, 1 eq) and N,N-diethylaniline (0.17 ml, 1.05 mmol, 1eq) in toluene (10 ml). The mixture is heated at reflux during 3 hours.After cooling, the resulting black mixture is poured on crushed ice. Theaqueous layer is extracted with AcOEt (3×10 ml) and the combined organiclayers are dried on anhydrous MgSO₄, filtered and evaporated underreduced pressure to yield 171 mg of2,6-dichloroimidazo[2,1-b][1,3]thiazole x172 as a yellow powder.

Yield: 85%.

LC-MS (MH⁺): 193/195/197.

66.3. Synthesis of1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one93

At room temperature, AlCl₃ (0.237 g, 1.78 mmol, 2 eq) is added to asolution of 2,6-dichloroimidazo[2,1-b][1,3]thiazole x172 (0.171 g, 0.89mmol, 1 eq) and 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.185 g,1.06 mmol, 1.2 eq) in 1,4-dioxane (25 ml). The mixture is heated atreflux during 2 hours. After cooling, water (20 ml) is added and theaqueous layer is extracted with CH₂Cl₂ (3×20 ml). The combined organiclayers are dried on anhydrous MgSO₄, filtered and evaporated underreduced pressure. The crude is purified on silicagel (CH₂Cl₂/AcOEt: 9/1)yielding 200 mg of1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one93 as a white solid.

Yield: 74%.

LC-MS (MH⁺): 332/334/336.

Example 67 Synthesis of1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one17

67.1. Synthesis of (2-chloroimidazo[1,2-a]pyridin-3-yl)methanol x174.

NaBH₄ (1.52 g, 41.33 mmol, 1.5 eq) is added to a solution of2-chloroimidazo[1,2-a]pyridine-3-carbaldehyde x173 (4.96 g, 27.56 mmol,1 eq) in EtOH (100 ml). After 1 hour at room temperature, water (100 ml)is added and the aqueous layer is extracted with CH₂Cl₂ (3×50 ml). Thecombined organic layers are dried on anhydrous MgSO₄, filtered andevaporated under reduced pressure. The resulting white solid isrecrystallized in CH₂Cl₂/hexane to yield 3.9 g of(2-chloroimidazo[1,2-a]pyridin-3-yl)methanol x174.

Yield: 78%.

LC-MS (MH⁺): 183/185.

67.2. Synthesis of1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one17

1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one17 is synthesized according to the procedure described in example 36.4.

Yield: 8.5%.

LC-MS (MH⁺): 292/294.

Example 68 Synthesis of1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one 95

68.1. Synthesis of 7-methyl-3H-imidazo[4,5-b]pyridine x176.

Raney Nickel (2.5 g) is added to a mixture of commercially available4-methyl-3-nitro-pyridin-2-ylamine x175 (7.0 g, 45.7 mmol) in methanol(300 ml), and the obtained reaction mixture is hydrogenated in the Parrapparatus at the hydrogen pressure 3 atm until the total conversion ofcompound x175 is attained for approximately 1.5-2 h. The catalyst isseparated by filtration, the filtrate is washed with methanol, and thealcohol solution is evaporated to dryness. CH(OMe)₃ (100 ml) and PTSA(0.5 g) are added to the residue, and an air reflux condenser ismounted. The apparatus is argon-blown, and the obtained reaction mixtureis heated to 125° C. under vigorous stirring for 10 h. The formedsolution is evaporated, and the residue is dissolved in 5% HCl (100 ml).The solution is refluxed for 1 h and evaporated to one-third volume. Thesolution is neutralized to pH 7 and extracted with 10% tert-butanol inchloroform (4×100 ml). The organic layer is dried over anhydrous Na₂SO₄,and the solvent is evaporated. The residue is purified by chromatographyon silicagel (chloroform/methanol) to afford7-methyl-3H-imidazo[4,5-b]pyridine x176.

Yield: 70%.

LC-MS (MH⁺): 134.

68.2. Synthesis of 3H-imidazo[4,5-b]pyridine-7-carboxylic acid x177

Na₂CO₃ (3.3 g, 1 eq, 31.5 mmol) and water (200 ml) are added to product7-methyl-3H-imidazo[4,5-b]pyridine x176 (4.2 g, 31.5 mmol). The reactionmixture is heated until boiled, which caused its transformation into asolution. KMnO₄ (12.5 g, 2.5 eq, 78.9 mmol) is added in small portionsto the obtained boiling solution. After KMnO₄ is added completely, thereaction mixture is additionally kept at 100° C. for 1 h and cooled to50-60° C. MnO₂ is filtered off, and the residue is additionally washedwith hot water (2×50 ml) on a filter. The obtained aqueous solution isevaporated in vacuum to a volume of 50 ml, cooled to 5° C., andacidified with 10% HCl to pH 2-3. The obtained suspension is kept at 5°C. for 1 h. The formed precipitate is separated by filtration, washedwith ice-cold water (2×10 ml), and vacuum-dried (1 mm Hg) over P₂O₅overnight to give 2.06 g of 3H-imidazo[4,5-b]pyridine-7-carboxylic acidx177.

Yield: 40%.

LC-MS (MH⁺): 164.

The following compound may be synthesized according to the same method:

x178 2-methyl-1H-imidazo[4,5-b]pyridine- LC-MS (MH⁺): 178 7-carboxylicacid

68.3. Synthesis of methyl 3H-imidazo[4,5-b]pyridine-7-carboxylate x179

Absolute methanol (30 ml) is added to acid x177 (2.0 g). ConcentratedH₂SO₄ (4 ml) is added to the obtained suspension at 0° C. The reactionmixture is refluxed under protection from the air moisture and vigorousstirring for 10 h. After 3 h the solid is completely dissolved. The nextmorning the reaction mixture is evaporated to half-volume in the vacuumof a rotary evaporator and neutralized under cooling with ice withaqueous ammonia to pH 8-9. The formed precipitate is quickly separatedby filtration, washed with ice-cold water (2×30 ml), and dried over P₂O₅overnight to afford 1.74 g of methyl3H-imidazo[4,5-b]pyridine-7-carboxylate x179.

Yield: 80%.

LC-MS (MH⁺): 257.

The following compound may be synthesized according to the same method:

x180 methyl 2-methyl-1H-imidazo[4,5-b]pyridine- LC-MS (MH⁺): 1927-carboxylate

68.4. Synthesis of the mixture of methyl3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate and methyl1-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate (75/25) x181

60% NaH in mineral oil (0.42 g, 1.1 eq, 10.6 mmol) is added in argonunder vigorous stirring at 0° C. to a mixture methyl3H-imidazo[4,5-b]pyridine-7-carboxylate x179 (1.7 g, 9.6 mmol) inabsolute DMF (30 ml). The mixture is stirred at the same temperature for20 min, and a solution, which contained a mixture of p-methoxybenzylchloride (1.8 g, 1.2 eq, 11.5 mmol) and tetrabutylammonium bromide (0.62g, 0.2 eq, 1.9 mmol) in absolute DMF (10 ml). The reaction mixture isstirred at 5° C. for 3 h and then at room temperature for 16 h. Then DMFis evaporated at 45° C. at the residual pressure 1 mmHg. The residue isdistributed in the system 10% aqueous NaH₂PO₄-ethyl acetate. The aqueouslayer is additionally subjected to extraction with ethyl acetate. Thecombined organic extracts are dried over anhydrous Na₂SO₄ andevaporated. The residue is purified by chromatography on silicagel(dichloromethane/ethanol) to afford 2.0 g of the 75/25 regioisomericmixture of methyl3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate and methyl1-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate x181. Wefound that it is more advantageous to separate the isomers at the nextstep in this case, i.e., after reduction of the ester function into thealcohol one.

Yield: 70%.

LC-MS (MH⁺): 298.

The following compound may be synthesized according to the same method:

x182 mixture of methyl 3-(4-methoxybenzyl)-2-methyl-3H- LC-MSimidazo[4,5-b]pyridine-7-carboxylate and methyl 1-(4- (MH⁺):methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7- 312 carboxylate

68.5. Synthesis of[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x183.

Compound x181 (1.95 g, 6.56 mmol, 75/25 mixture of the two regioisomers)is dissolved in absolute ethanol. NaBH₄ (0.48 g, 4 eq, 12.76 mmol) isadded at 5° C. under stirring. The cooling bath is removed after 4 h,and the reaction mixture is allowed to heat up to room temperature. Thestirring is continued at this temperature for 20 h. The reaction mixtureis evaporated in the vacuum of a rotary evaporator at 35° C., and theresidue is partitioned in an ethyl acetate/saturated aqueous NaHCO₃mixture. The organic layer is dried with anhydrous sodium sulfate andevaporated. The crude reaction mixture is purified by chromatography onsilicagel (dichloromethane/methanol). Evaporation of the correspondingfractions followed by vacuum drying affords[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x183 (1.06g).

Yield: 59%.

LC-MS (MH⁺): 270.

The following compound may be synthesized according to the same method:

x184 [3-(4-methoxybenzyl)-2-methyl-3H- LC-MS (MH⁺): 284imidazo[4,5-b]pyridin-7-yl]methanol

68.6. Synthesis of1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex187

[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x183 (0.5 g,1.86 mmol) is dissolved in dichloromethane (20 ml). SOCl₂ (2 ml) isadded dropwise. The reaction mixture is refluxed for 1 h. The volatilesare distilled off in the vacuum of a rotary evaporator. Then 50 ml ofchloroform is distilled off additionally from the residue. The residualchloroform solution is added dropwise at 0° C. to a vigorously stirredsaturated aqueous solution of NaHCO₃. The organic phase is separated,dried with anhydrous sodium sulfate, and evaporated. The residue is keptunder 1 mmHg for 1.5 h at 40° C. to afford7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine x185sufficiently pure for the next step.

7-(chloromethyl)-3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridinex186 may be obtained according to the same method.

4-propylpyrrolidin-2-one x1 (0.26 g, 1.1 eq with respect to x183, 2.0mmol) is dissolved in absolute DMF (10 ml). Then 60% NaH (0.080 g, 1.1eq, 2.0 mmol) is added at 0° C. in a flow of argon. The reaction mixtureis stirred for 10 min at 0° C., and then for 10 min at room temperatureto complete the reaction. Then the mixture is cooled again to 0° C. Asolution of the chloride x185 prepared above in absolute DMF (5 ml)additionally containing 0.1 g (0.2 eq, 0.32 mmol) of tetrabutylammoniumbromide is added dropwise to the obtained suspension. The reactionmixture is stirred at 5° C. for 4 h. The cooling bath is removed, andthe stirring is continued at room temperature overnight. The nextmorning the DMF is evaporated at 45° C. under 1 mmHg. The residue ispartitioned in 10% aqueous NaH₂PO₄/ethyl acetate mixture. The aqueouslayer is subjected to additional extraction with ethyl acetate. Thecombined extracts are dried with anhydrous sodium sulfate andevaporated. The residue is purified by chromatography to afford 0.6 g of1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex187.

Yield: 85% (calculated from alcohol x183)

LC-MS (MH⁺): 458.

The following compounds may be synthesized according to the same method:

x188 1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5- LC-MS (MH⁺): 412b]pyridin-7-yl]methyl}-4- phenylpyrrolidin-2-one x1891-{[3-(4-methoxybenzyl)-2-methyl-3H- LC-MS (MH⁺): 393imidazo[4,5-b]pyridin-7-yl]methyl}- 4-propylpyrrolidin-2-one

68.7. Synthesis of1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one 95

A solution containing1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex187 (0.6 g), anisole (0.4 ml) and concentrated H₂SO₄ (0.2 ml) intrifluoroacetic acid (4 ml) is stirred in a flow of argon at 20° C. for2 h. The homogeneous reaction mixture is added dropwise at 0° C. to amixture of a saturated aqueous solution of NaHCO₃ (50 ml) and ethylacetate (50 ml). The organic layer is separated. The aqueous one (pH˜8)is subjected to additional extraction with chloroform containing 10% oftert-butanol. The combined organic layers are dried with anhydroussodium sulfate and evaporated. The residue is purified by chromatographyon silicagel (chloroform/methanol) to afford1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one 95(0.34 g).

Yield: 85%.

LC-MS (MH⁺): 259.

Compounds 1, 2, 96 and 102 may be synthesized according to the samemethod.

Example 69 Synthesis of4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one103

69.1. Synthesis of N-(4-methoxybenzyl)-2-nitroethylene-1,1-diamine x191.

Hydrochloride x190 (from Chem. Ber. 1963, 96, 3306; Arch. Pharm. 1986,319 (1), 14; J. Heterocycl. Chem. 1995, 32 (3) 963; Synthesis (GE) 1991,10, 835; 6.14 g, 39.7 mmol) is dissolved in absolute methanol (90 ml). Asolution of sodium methoxide [freshly prepared from 0.96 g (1.05 eq) ofsodium] in absolute methanol (20 ml) is added dropwise at 0° C. Theobtained suspension is stirred additionally for 20 min at 0° C. NaCl isfiltered off, and the filtrate is evaporated to a volume of 30 ml.4-Methoxyaniline (10.9 g, 2 eq, 79.4 mmol) is added, and the reactionmixture is refluxed for 1.5 h. The reaction mixture is evaporated to aminimum volume and diluted with 150 ml ether. The formed precipitate isseparated by filtration, washed with ether, and vacuum-dried to afford8.4 g of N-(4-methoxybenzyl)-2-nitroethylene-1,1-diamine x191.

Yield: 95%.

LC-MS (MH⁺): 224.

69.2. Synthesis of ethyl2-[(4-methoxybenzyl)amino]-3-nitro-6-(trifluoromethyl)isonicotinate x193

A mixture of ethyl 5,5,5-trifluoro-2,4-dioxopentanoate x192 (describedin the following work: Izvestiya Akademii Nauk SSSR, SeriyaKhimicheskaya (Russian Chemical Bulletin), 1990, 6. 1410-1414 (seeKondrat'ev, P. N.; Skryabina, Z. E.; Saloutin, V. I.; Rudaya, M. N.;Sinitsyna, T. A.; Pashkevich, K. I.; BACCAT; Bull. Acad. Sci. USSR Div.Chem. Sci. (Engl. Transl.); 39; 6; 1990; 1273-1277; IASKA6); 1.8 g, 8.5mmol) and (E)-N-(4-methoxybenzyl)-2-nitroethylene-1,1-diamine x191 (2.1g, 1.1 eq, 9.3 mmol) in absolute ethanol (70 ml) is refluxed in a flowof argon for 48 h. The reaction mixture is evaporated to dryness. Theresidue is dissolved in chloroform. The solution is filtered, and thefiltrate is evaporated. The residue is purified by chromatography onsilicagel (CCl₄/MeCN) to give 2.7 g of ethyl2-[(4-methoxybenzyl)amino]-3-nitro-6-(trifluoromethyl)isonicotinatex193.

Yield: 80%.

LC-MS (MH⁺): 400.

The following compounds may be synthesized according to the same method:

x194 ethyl 2-[(4-methoxybenzyl)amino]-3-nitro-6- LC-MS (MH⁺): 408phenylisonicotinate x195 ethyl 2-[(4-methoxybenzyl)amino]-6-methyl-LC-MS (MH⁺): 346 3-nitroisonicotinate

69.3. Synthesis of ethyl3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylatex196

Ethyl2-[(4-methoxybenzyl)amino]-3-nitro-6-(trifluoromethyl)isonicotinate x193(2.6 g, 6.5 mmol) is dissolved in methanol (100 ml), and Raney nickel(0.8 g) is added. The starting compound is hydrogenated in a Parrapparatus under a hydrogen pressure of 3 atm until the conversion ofx193 is complete (1.5-2 h). The catalyst is filtered off and washed withmethanol. The filtrate is evaporated to dryness. Triethyl orthoformate(100 ml) and p-toluene sulfonic acid (0.15 g) are added. The flask isequipped with a reflux condenser. The apparatus is flushed with argon,and the obtained reaction mixture is heated under vigorous stirring to150° C. for 6 h. The reaction solution is evaporated in vacuum. Theresidue is partitioned between dichloromethane and a saturated aqueoussolution of NaHCO₃. The organic layer is dried with anhydrous sodiumsulfate and evaporated. The target product is purified by chromatographyon silicagel (dichloromethane/acetone) to afford 1.5 g of ethyl3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylatex196.

Yield: 60%.

LC-MS (MH⁺): 380.

The following compound may be synthesized according to the same method:

x197 ethyl 3-(4-methoxybenzyl)-5-phenyl-3H- LC-MS (MH⁺):imidazo[4,5-b]pyridine-7-carboxylate 388 x198 ethyl3-(4-methoxybenzyl)-5-methyl-3H- LC-MS (MH⁺):imidazo[4,5-b]pyridine-7-carboxylate 326

69.4. Synthesis of[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanolx199

This step is realized as described in example 68.5. for the synthesis of[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x183 withthe use of 3 eq of NaBH₄ for 1.45 g (3.8 mmol) of ethyl3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylatex196. Purification by chromatography on silicagel affords 0.58 g of[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanolx199.

Yield: 45%.

LC-MS (MH⁺): 338.

The following compound may be synthesized according to the same method:

x200 [3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5- LC-MS (MH⁺):b]pyridin-7-yl]methanol 346 x201[3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5- LC-MS (MH⁺):b]pyridin-7-yl]-methanol 284

69.5. Synthesis of1-{[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex205

[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanolx199 (0.55 g, 1.63 mmol) is dissolved in dichloromethane (20 ml). SOCl₂(2 ml) is added dropwise. The reaction mixture is refluxed for 1 h. Thevolatiles are rotary-evaporated. Then 50 ml of chloroform isadditionally distilled off from the residue. The resulting chloroformsolution is added dropwise at 0° C. under vigorous stirring to saturatedaqueous NaHCO₃. The organic phase is separated, dried with anhydroussodium sulfate, evaporated, and dried under 1 mmHg for 1.5 h at 40° C.7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridinex202 (0.55 g, 95%) sufficiently pure for the next step is obtained.

7-(chloromethyl)-3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridinex203 and7-(chloromethyl)-3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridinex204 may be obtained according to the same method.

4-propylpyrrolidin-2-one x1 (0.22 g, 1.1 eq with respect to x199, 1.7mmol) is dissolved in absolute THF (10 ml). A 1.06 M solution of Li-HMDSin THF (1.76 ml, 1.1 eq, 1.87 mmol) is added at −78° C. in a flow ofargon. The reaction mixture is stirred for 15 min at −30° C. and cooledagain to −78° C. A solution of7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridinex202 in absolute THF (10 ml) is added dropwise at this temperature. Thereaction mixture is allowed to heat up slowly to room temperature. Inorder to complete the reaction, the reaction mixture is refluxed thenext morning for 1 h, and then partitioned between saturated aqueousNH₄Cl and ethyl acetate. The organic layer is dried with anhydroussodium sulfate and evaporated. The product is purified by HPLC(water/acetonitrile) to afford 0.14 g of1-{[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex205 (0.14 g).

Yield: 20%.

LC-MS (MH⁺): 447.

The following compound may be synthesized according to the same method:

x206 1-{[3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5- LC-MSb]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one (MH⁺): 489 x2071-{[3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5- LC-MSb]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one (MH⁺): 393

69.6. Synthesis of4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one103

This step is realized as described in example 68.7. for the synthesis of1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one 95. Inthis case, the deprotection occurs very slowly. In order to complete thereaction, the reaction mixture is kept in a flow of argon at 37° C. for5 days. From 0.13 g of compound x205, 60 mg of4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one103 are obtained.

Yield: 70%.

LC-MS (MH⁺): 327.

Compounds 97, 98 and 101 may be synthesized according to the samemethod.

Example 70 Synthesis of1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one99

70.1. Synthesis of methyl6-bromo-1H-imidazo[4,5-b]pyridine-7-carboxylate x209.

Absolute methanol (30 ml) is added to6-bromo-1H-imidazo[4,5-b]pyridine-7-carboxylic acid x208 (Zerenex; 2.2g, 9.1 mmol). Concentrated H₂SO₄ (4 ml) is added to the obtainedsuspension at 0° C. The reaction mixture is refluxed under protectionfrom the air moisture and vigorous stirring for 10 h. The reactionmixture is then evaporated to half-volume in the vacuum of a rotaryevaporator and neutralized under cooling with ice with aqueous ammoniato pH 8-9. The formed precipitate is quickly separated by filtration,washed with ice-cold water (2×30 ml), and dried over P₂O₅ at 1 mmHgovernight to afford methyl6-bromo-1H-imidazo[4,5-b]pyridine-7-carboxylate x209 (1.63 g).

Yield: 70%.

LC-MS (MH⁺): 257.

70.2. Synthesis of methyl6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate x210

Methyl 6-bromo-1H-imidazo[4,5-b]pyridine-7-carboxylate x209 (1.425 g,5.56 mmol) is suspended in absolute THF (40 ml) and 60% NaH (0.235 g,1.05 eq, 5.84 mmol) is added at 0° C. under vigorous stirring. Thereaction mixture is stirred for 15 min until compound x209 is completelydissolved. Tetrabutylammonium bromide (0.54 g, 0.3 eq, 1.67 mmol) isadded to the obtained solution. Then p-methoxybenzyl chloride (0.96 g,1.1 eq, 6.12 mmol) is added dropwise. The reaction mixture is refluxedin a flow of argon for 5 h. The next morning the reaction mixture isevaporated. The residue is dissolved in ethyl acetate. A solid isfiltered off. The organic phase is washed with 10% NaH₂PO₄, dried withanhydrous sodium sulfate and evaporated. The residue is purified bychromatography on silicagel to afford 1.26 g of protected compound x210.

Yield: 60%.

LC-MS (MH⁺): 377.

70.3. Synthesis of[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x211

Methyl6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate x210(1.2 g, 3.19 mmol) is dissolved in absolute ethanol. NaBH₄ (0.36 g, 3eq, 9.57 mmol) is added at 5° C. under stirring. The cooling bath isremoved after 4 h, and the reaction mixture is allowed to heat up toroom temperature. The stirring is continued at this temperature for 20h. The reaction mixture is evaporated in the vacuum of a rotaryevaporator at 35° C., and the residue is partitioned in ethylacetate/saturated aqueous NaHCO₃ mixture. The organic layer is driedwith anhydrous sodium sulfate and evaporated. The crude product ispurified by chromatography on silicagel (dichloromethane/methanol) toafford 0.72 g of[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanolx211.

Yield: 65%.

LC-MS (MH⁺): 349.

70.4. Synthesis of1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex213

Primary alcohol x211 (0.61 g, 1.75 mmol) is dissolved in dichloromethane(20 ml) and SOCl₂ (2 ml) is added dropwise. The reaction mixture isrefluxed for 1 h. The volatiles are distilled off in the vacuum of arotary evaporator. Then 50 ml of chloroform are distilled offadditionally from the residue. The residual chloroform solution is addeddropwise at 0° C. to a vigorously stirred saturated aqueous solution ofNaHCO₃. The organic phase is separated, dried with anhydrous sodiumsulfate, and evaporated. The residue is kept under 1 mmHg for 1.5 h at40° C. The obtained6-bromo-7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridinex212 (0.59 g, 94%) is sufficiently pure for the next step.

4-propylpyrrolidin-2-one x1 (0.23 g, 1.1 eq, 1.8 mmol) is dissolved inabsolute DMF (10 ml). Then 60% NaH (0.072 g, 1.1 eq, 1.8 mmol) is addedat 0° C. in a flow of argon. The reaction mixture is stirred for 10 minat 0° C., and then for 10 min at room temperature to complete thereaction. The mixture is cooled again to 0° C. and a solution of6-bromo-7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridinex212 (0.59 g, 1 eq) in absolute DMF (5 ml) additionally containing 0.1 g(0.2 eq, 0.32 mmol) of tetrabutylammonium bromide is added dropwise tothe obtained suspension. The reaction mixture is stirred for 4 h at 5°C., then overnight at room temperature. The DMF is evaporated at 45° C.under 1 mmHg. The residue is partitioned in 10% aqueous NaH₂PO₄/ethylacetate mixture. The aqueous layer is subjected to additional extractionwith ethyl acetate. The combined extracts are dried with anhydroussodium sulfate and evaporated. The residue is purified by chromatographyon silicagel to afford 0.52 g of1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex213.

Yield: 65% (calculated from alcohol x211).

LC-MS (MH⁺): 458.

70.5. Synthesis of1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one99

A solution containing1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex213 (0.5 g, 0.1 mmol), anisole (0.4 ml) and concentrated H₂SO₄ (0.2 ml)in trifluoroacetic acid (4 ml) is stirred in a flow of argon at 20° C.for 2 h. The homogeneous reaction mixture is added dropwise at 0° C. toa mixture of a saturated aqueous solution of NaHCO₃ (50 ml) and ethylacetate (50 ml). The organic layer is separated. The aqueous one (pH ˜8)is subjected to additional extraction with chloroform containing 10% oftert-butanol. The combined organic layers are dried with anhydroussodium sulfate and evaporated. The residue is purified by chromatographyon silicagel (chloroform/methanol) to afford 0.31 g of1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one99.

Yield: 85%.

LC-MS (MH⁺): 337/339.

Example 71 Synthesis of1-[(6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one105

71.1. Synthesis of[3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methanolx214

A reactor containing[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x211(0.55 g, 1.58 mmol) in propionitrile (4 ml) and methanol (1 ml) ischarged sequentially with phenylboronic acid (0.24 g, 1.25 eq, 1.98mmol), sodium carbonate (0.34 g) in water (1.6 ml, 2 eq as a 2 M aqueoussolution, 3.16 mmol), and tetrabutylammonium bromide (0.1 g, 0.2 eq,0.32 mmol). The content of the reactor is evacuated several times andsubsequently flushed with argon. Thentetrakis(triphenylphosphine)palladium(0) (0.09 g, 5 mol %, 0.08 mmol) isadded. The reactor is equipped with a reflux condenser. The wholeapparatus is evacuated twice and subsequently flushed with argon. Thereaction mixture is kept for 26 h in a flow of argon under vigorousstirring at a bath temperature of 110° C. In the process, the stronglyheterogeneous reaction mixture transforms into a solution. When thereaction is complete, the obtained solution is partitioned in 10%aqueous NaH₂PO₄/ethyl acetate mixture. The organic layer is additionallywashed with saturated aqueous NaHCO₃, dried with anhydrous sodiumsulfate and evaporated in vacuum. The obtained compound is purified bychromatography on silicagel (chloroform/isopropanol) to afford 0.46 g of[3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methanolx214.

Yield: 85%.

LC-MS (MH⁺): 346.

71.2. Synthesis of1-{[3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex216

This compound is synthesized according to the method described inexample 70.4 with7-(chloromethyl)-3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridinex215 as intermediate.

Yield: 87%.

LC-MS (MH⁺): 455.

71.3. Synthesis of1-[(6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one105

This compound is synthesized according to the method described inexample 70.5, using1-{[3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex216 as starting material.

Yield: 85%.

LC-MS (MH⁺): 335.

Example 72 Synthesis of1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one104

72.1. Synthesis of[3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methanolx217

The bromine-containing alcohol x211 (1.7 g, 4.9 mmol) is dissolved inabsolute freshly distilled dioxane (15 ml).[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.072 g, 2mol %, 0.098 mmol) is added in a flow of argon. A 1.2 M solution ofZnMe₂ in toluene (8.2 ml, 2 eq, 9.8 mmol) is added dropwise to theobtained suspension. The reaction mixture is refluxed in a flow of argonfor 1.5 h and neutralized with a saturated aqueous solution of K₂CO₃.Ethyl acetate (100 ml) is added. The inorganic solid is filtered off.The organic layer is separated, dried with anhydrous sodium sulfate, andevaporated in vacuum. The obtained product is purified by chromatographyon silicagel (chloroform/methanol) to afford 1.18 g of[3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methanolx217.

Yield: 85%.

LC-MS (MH⁺): 284.

72.2. Synthesis of1-{[3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex219

This compound is synthesized according to the method described inexample 70.4, with7-(chloromethyl)-3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridinex218 as intermediate.

Yield: 87%.

LC-MS (MH⁺): 393.

72.3. Synthesis of1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one104

This compound is synthesized according to the method described inexample 70.5, using1-{[3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex219 as starting material.

Yield: 85%.

LC-MS (MH⁺): 273.

Example 73 Synthesis of1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one100

73.1. Synthesis of 7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine x221.

Raney Ni (1.5 g) is added to a mixture of commercially availablenitrogen-containing 4-methyl-3-nitropyridin-2-amine x220 (4.0 g, 26.1mmol) in methanol (150 ml), and the obtained reaction mixture ishydrogenated in the Parr apparatus at the hydrogen pressure 3 atm untilthe total conversion of compound x220 is attained for approximately1.5-2 h. The catalyst is separated by filtration, the filtrate is washedwith methanol, and the alcohol solution is evaporated to dryness. Theresidue is dissolved in sulfolane (10 ml), then PhC(OMe)₃ (5.7 g, 1.2eq, 31.3 mmol) and PTSA (0.3 g) are added, and an air reflux condenseris mounted. The apparatus is argon-blown, and the obtained reactionmixture is heated to 165° C. under vigorous stirring for 10 h. Water(100 ml), saturated aqueous NaHCO₃ (5 ml), and hexane (50 ml) are addedto the reaction mixture. The obtained suspension is stirred for 5 min,and the residue is separated by filtration. The residue is washed withwater (50 ml) and hexane (100 ml), and vacuum-dried over P₂O₅ to aconstant weight at 45° C. to give7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine x221 (2.2 g).

Yield: 40%.

LC-MS (MH⁺): 210.

The following compound may be synthesized according to the same method:

x222 2,7-dimethyl-3H-imidazo[4,5-b]pyridine LC-MS (MH⁺): 148

73.2. Synthesis of3-(4-methoxybenzyl)-7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine x223

Isomerically pure3-(4-methoxybenzyl)-7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine x223(2.3 g) is obtained following the experimental procedure of example70.2, using 2.1 g (10 mmol) of7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine x221.

Yield: 70%.

LC-MS (MH⁺): 330.

73.3. Synthesis of2-[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]-N,N-dimethylethylenaminex224

(Me₂N)₂CHOtBu (1.8 g, 1.5 eq, 10.2 mmol) is added in argon to a solutionof 3-(4-methoxybenzyl)-7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine x223(2.25 g, 6.8 mmol) in absolute 1,2-dimethoxyethane (7 ml), and theobtained solution is kept at 60° C. for 16 h. Then the solution isadditionally refluxed for 4 h. The reaction mixture is cooled to roomtemperature, diluted with hexane, and kept at 3° C. for 1 h. The formedprecipitate of enamine is separated by filtration, washed with hexane,and vacuum-dried to afford 2 g of2-[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]-N,N-dimethylethylenaminex224 (purity 90% according to the LC/MS data).

Yield: 70%.

LC-MS (MH⁺): 385.

73.4. Synthesis of3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehydex225

Sodium periodate (3.3 g, 3 eq, 15 mmol) is added under vigorous stirringto a suspension of2-[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]-N,N-dimethylethylenaminex224 (2 g, about 5 mmol) in a 1/1 water/THF mixture (60 ml). The mixtureis stirred at room temperature until the complete conversion of startingenamine is attained for approximately 5 h. Ethyl acetate (100 ml) andsaturated aqueous NaHCO₃ (50 ml) are added to the mixture. The mixtureis stirred, and the precipitate of inorganic salts is filtered off. Theorganic layer is separated from the obtained two-phase mixture and driedover anhydrous Na₂SO₄. The solution is evaporated, and the residue ispurified by chromatography on silicagel (dichloromethane/isopropanol) to1 g of3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehydex225.

Yield 60%.

LC-MS (MH⁺): 344.

73.5. Synthesis of1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex226

Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolvedin absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate(1 g) are added under vigorous stirring. After 15 min, the mixture isdiluted with ether (100 ml) and filtered. The solid on the filter iswashed with ether (2×50 ml). A solution of3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehydex225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. Thecombined solution is evaporated in the vacuum of a rotary evaporator.The residue is dissolved in methanol (10 ml), CH(OMe)₃ (0.5 ml) is addedand the obtained solution is stirred at room temperature for 16 h. Anexcess of NaBH₄ (1 g in several small portions) is then added undervigorous stirring for 20 min. The reaction mixture is evaporated in thevacuum of a rotary evaporator. The residue is partitioned between ethylacetate and water. The organic phase is separated, dried with anhydroussodium sulfate, and evaporated. The residue is dissolved in acetonitrile(10 ml), and the solution is refluxed for 24 h to complete thecyclization. The solvent is distilled off. The residue is purified bychromatography on silicagel (CCl₄/MeCN) to yield 0.79 g of1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex226.

Yield: 60%.

LC-MS (MH⁺): 414.

73.6. Synthesis of1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one100

Deprotection step of1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-onex226 is performed as described in example 68.7 to afford1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one100.

LC-MS (MH⁺): 335.

Example 74 Synthesis of4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one255

74.1 Synthesis of6-chloro-8-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazinex229 and6-chloro-7-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazinex230

In the absence of air moisture, the 3:1 regioisomeric mixture of6-chloro-4-methylpyridazin-3(2H)-one hydrazone x227 and6-chloro-5-methylpyridazin-3(2H)-one hydrazone x228 (7.88 g, 4.97 mmol,obtained according to R. J. Cregge, J. E. Coutant, U.S. Pat. No.4,578,464, 1986) is dissolved in TFA (77 ml) and kept under stirring atthe bath temperature 90° C. for 16 h. The reaction mixture is cooled,TFA is removed under reduced pressure, and the residue is dissolved indichloromethane (200 ml). The solution is washed with a saturated NaHCO₃solution and dried over anhydrous Na₂SO₄. The solution is evaporated andvacuum-dried to give the mixture of intermediates x229 and x230 in themolar ratio 2.6:1 according to the ¹H NMR data as a white solid mass.

Yield: 87% (10.24 g).

¹H NMR (DMSO-d₆): 2.44 (d, J=1.23 Hz), 2.69 (d, J=1.23 Hz), 7.66 (d,J=1.22 Hz), 8.59 (d, J=1.22 Hz).

74.2. Synthesis of8-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine x231 and7-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine x232

The mixture of intermediates x229 and x230 (10 g, 42.3 mmol) isdissolved in ethanol (640 ml). Pd/C (10%, 2.8 g) and aqueous ammonia(25%, 172 ml) are added, and the mixture is hydrogenated in the Parrapparatus under the hydrogen pressure 2 atm at room temperature for 50min. The reaction mixture is filtered through the Celite layer, andCelite is washed with ethanol. The combined extracts are evaporated, andthe residue is dissolved in chloroform. The solution is washed withbrine and dried over anhydrous Na₂SO₄. The solvent is removed underreduced pressure and the residue (8.6 g) is purified by chromatographyon silicagel (hexane/ethyl acetate 1/1) to give the 1:3 mixture ofisomers x231 and x232 (0.48 g), the 2:1 mixture of isomers x231 and x232(1.16 g), and isomer x232 (1.70 g; yield: 27.5% calculated for startingisomer x230).

Total yield: 39%.

x232: ¹H NMR (DMSO-d₆): 2.46 (d, J=1.22 Hz, 3H), 8.35 (t, J=1.71 Hz,1H), 8.78 (d, 1.96 Hz, 1H).

74.3 Synthesis ofN,N-dimethyl-2-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]ethylenaminex233

Brederick's reagent (1-tert-butoxy-N,N,N,N-tetramethylmethanediamine,2.8 ml, 13.5 mmol, 1.6 eq) is added under stirring to a solution of7-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine x232 (1.70g, 8.4 mmol) in dry DME (32 ml). The reaction mixture is refluxed for 4h, cooled to room temperature and stirred overnight for 16 h. The formedprecipitate is separated by filtration and dried to give crudeN,N-dimethyl-2-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]ethylenaminex233 (0.44 g) as a yellow powder. The Brederick's reagent (0.5 ml, 2.4mmol) is additionally added to the mother liquor, which containedunreacted regioisomer x232 according to the TLC data, and the obtainedmixture is refluxed for 8 h. Then the reaction mixture is cooled to roomtemperature, diluted with hexane (10 ml), and kept overnight. The formedprecipitate is separated by filtration and dried to give additionallyintermediate x233 (0.32 g,).

Total yield: 35% (0.76 g).

¹H NMR (DMSO-d₆): 2.94 (s, 6H), 5.13 (d, J=13.4 Hz, 1H), 7.67-7.70 (m,2H), 8.8 (s, 1H).

N,N-dimethyl-2-(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)ethylenaminex234 may be prepared according to the same method.

74.4. Synthesis of3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde x235

A finely-ground powder of NalO₄ is added to a solution of7-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine x233 (0.52g, 2.0 mmol) in absolute methanol (42 ml). The reaction mixture isstirred at room temperature for 1.5 h and diluted with an equal volumeof dichloromethane. The mixture is filtered through the Celite layer,and the solvents are removed under reduced pressure. The residue (0.5 g)is purified by chromatography on silicagel (hexane/ethyl acetate 3/2) toyield 0.34 g of3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde x235as a white solid.

Yield: 78%.

¹H NMR (CDCl₃): 8.70 (d, J=1.95 Hz, 1H); 9.03 (d, J=1.71 Hz, 1H), 10.17(s, 1H).

3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde x236 may beprepared according to the same method.

74.5. Synthesis of4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one255

Methyl 4-amino-3-phenylbutanoate hydrochloride x11 (0.19 g, 0.83 mmol,1.05 eq) is added to a solution of aldehyde x235 (0.17 g, 0.79 mmol) indry dichloroethane (DCE) (7.8 ml). The mixture is kept at roomtemperature for 30 min, cooled to 10-12° C., and a solution oftriethylamine (0.15 ml, 0.83 mmol, 1.05 eq) in dry DME (2.5 ml) is addeddropwise. The mixture is additionally stirred at the same temperaturefor 1 h and cooled to 0-5° C. Then STAB (0.23 g, 1.10 mmol, 1.4 eq) isadded in portions under vigorous stirring. The mixture is additionallystirred at 0-5° C. for 30 min and kept at room temperature overnight.Then the mixture is heated to 60° C. for 2 h and cooled to roomtemperature. An equal volume of dichloromethane is added, and themixture is washed with 10% K₂CO₃ (2×10 ml). The mixture is dried overanhydrous Na₂SO₄ and evaporated. The oily residue is triturated withether, and the formed crystals are separated by filtration, washed twicewith ether, and vacuum-dried to give white fine-crystalline4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one255.

Yield: 36% (0.101 g).

LC-MS (MH⁺): 362.

Example 75 Synthesis of4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one258

75.1. Synthesis ofN,N-dimethyl-2-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]ethylenamineb1502.5a.

The isomeric mixture (3 g, 6.3 mmol.) of8-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine x231 and7-methyl-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine x232 isdissolved in DME (30 ml), and Brederick's reagent (1.7 g, 10.0 mmol, 1.6eq) is added to the obtained solution. The reaction mixture is stirredat 60-65° C. for 4 h, cooled to room temperature, and excess solventsare removed under reduced pressure. The residue is vacuum-dried to givethe mixture of enamine x237 and starting isomer x232 (2.24 g) in themolar ratio 2.5:1 according to the ¹H NMR data. This mixture is used forthe next step without further purification.

2-[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-N,N-dimethylethylenaminex238 may be synthesized according to the same method.

75.2 Synthesis of3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde x239

The previous mixture (x237 and starting isomer x232) is dissolved inabsolute methanol (137 ml), and finely-ground NalO₄ (4.24 g, 19.8 mmol)is added to the obtained solution. The reaction mixture is stirred atroom temperature for 4.5 h, diluted with an equal volume ofdichloromethane, and filtered through the Celite layer. The solvents areremoved under reduced pressure. The residue is purified bychromatography on silicagel (hexane/ethyl acetate 1/1) to yield3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde x239as a white solid substance (0.42 g).

Yield: 31%.

¹H NMR (DMSO-d₆): 8.04 (d, J=4.40 Hz, 1H), 9.14 (d, J=4.40 Hz, d, 1H),10.49 (s, 1H).

75.3. Synthesis of4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one258

4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one258 is synthesized as described in example 74.5 from the aldehyde x239(0.182 g. 0.84 mol), methyl 3-(aminomethyl)hexanoate hydrochloride x12(0.165 g, 0.84 mmol), TEA (0.123 ml, 0.885 mmol), and NaBH(OAc)₃ (0.25g, 1.18 mmol) in DCE (11.3 ml).

Yield: 30% (0.084 g).

LC-MS (MH⁺): 258.

Compound 257 may be synthesized according to the same method.

Example 76 Synthesis of4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one259

76.1. Synthesis of 8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazinex241.

6-chloro-8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x240 isdissolved in ethanol (300 ml), and 10% Pd/C (0.9 g) and 25% aqueousammonia (60 ml) are added. The mixture is hydrogenated in the Parrapparatus under hydrogen pressure 2.5 atm at room temperature for 1 h10. The reaction mixture is filtered through a Celite layer, which iswashed with ethanol. The combined filtrates are evaporated, and theresidue is dissolved in dichloromethane. The solution is washed withbrine and dried over anhydrous Na₂SO₄. The solvent is removed underreduced pressure to afford 2.9 g of8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x241.

Yield: 85%.

¹H NMR (DMSO-d₆): 2.67 (d, J=1.23 Hz, 3H), 7.54-7.64 (m, 4H), 8.37-8.39(m, 2H), 8.61 (d, J=4.4 Hz, 1H).

76.2. Synthesis ofN,N-dimethyl-2-(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)ethylenaminex242

Brederick's reagent (3.2 g, 18 mmol) is added to a solution of8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x241 (2.9 g, 18 mmol)in DME (26 ml), and the reaction mixture is stirred at 60° C. for 2 h.Then the mixture is cooled to room temperature, the solvents are removedunder reduced pressure, and the residue (4.9 g) ofN,N-dimethyl-2-(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)ethylenaminex242 is used for the next step without additional purification.

2-(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-N,N-dimethylethylenaminex243 and2-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-N,N-dimethylethylenaminex244 may be synthesized according to the same method.

76.3. Synthesis of3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde x245 and methyl3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate x246

Crude enamine x242 is dissolved in absolute ethanol (86 ml). Afinely-ground NalO₄ powder (8.86 g, 41.4 mmol) is added, and thereaction mixture is vigorously stirred at room temperature for 4 h. Thenthe mixture is diluted with an equal volume of dichloromethane, filteredthrough a Celite layer, and the solvents are removed under reducedpressure. The residue (5.9 g) is purified by chromatography on silicagel(ethyl acetate) to afford, according to the ¹H NMR data, a 2:1 mixtureof 3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde x245 andmethyl 3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate x246 (1.2g).

¹H NMR (DMSO-d₆): 4.03 (s), 7.57-7.67 (m), 7.85 (t, J=4.16 Hz),8.33-8.39 (m), 8.89 (d, J=4.41 Hz), 9.01 (d, J=4.15 Hz), 10.55 (s).

The mixture of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehydex247 and methyl 6-chloro[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylatex248 (1/2 ratio) may be obtained according to the same method.

LC-MS (MH⁺): 187 and 213.

76.4. Synthesis of4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one259

This step is realized as described in example 74.5 from the previouslysynthesized mixture of x245 and x246 (0.60 g), methyl4-amino-3-phenylhexanoate hydrochloride x11 (0.39 g, 1.7 mmol), TEA(0.23 ml, 1.66 mmol), and NaBH(OAc)₃ (0.56 g, 2.6 mmol) in DCE (30 ml).The crude compound is purified by chromatography on silicagel (ethylacetate) to afford 0.57 g of product4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one259.

Yield: 90%.

LC-MS (MH⁺): 370.

Compounds 257 and 261 may be synthesized according to the same method.

Example 77 Synthesis of1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one260

77.1. Synthesis of(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)(methoxy)methanolx249

Analogously to the procedure described in example 76.3, from a solutionof2-(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-N,N-dimethylethylenaminex243(1.84 g, 6.14 mmol) in absolute methanol (30 ml) and NalO₄ (3.92 g,18.4 mmol) under stirring for 24 h. Semiacetal x249 (0.73 g) is obtainedafter purification by chromatography on silicagel (hexane/ethyl acetate1/1).

Yield: 41%.

¹H NMR (DMSO-d₆): 3.47 (s, 3H), 6.05 (d, J=7 Hz, 1H), 7.41 (s, 1H), 7.51(d, J=7.34 Hz, 1H), 7.57-7.66 (m, 4H).

The same method is used for the synthesis of[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl](methoxy)methanolx250 but in this case, the compound is also observed as its hydrate andits methyl hemiacetal.

77.2. Synthesis of1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one260

This step is realized as described in example 74.5 from semiacetal x249(0.37 g, 1.3 mmol), methyl 3-(aminomethyl)hexanoate hydrochloride x12(0.26 g, 1.33 mmol), triethylamine (0.19 ml, 1.33 mmol), and NaHB(OAc)₃(0.38 g, 1.8 mmol) in DCE (20 ml). After purification by chromatographyon silicagel (hexane/ethyl acetate 1/1),1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one260 (0.23 g) is obtained.

Yield: 49%.

LC-MS (MH⁺): 370/372.

Compounds 262 and 263 may be synthesized according to the same method.

Example 78 Synthesis of 1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one157

A solution of 5-hydroxy-4-propyldihydrofuran-2(3H)-one x252 (0.44 g, 3.0mmol) in dry DCE (8 ml), DIEA (0.364 g, 2.8 mmol), and several dropsAcOH is added to a suspension of 1-isoxazol-4-ylmethanaminehydrochloride x251 (0.46 g, 3.0 mmol) in dry DCE, and NaHB(OAc)₃ (0.976g, 2.3 mmol) is added in 50 min. The reaction mixture is stirred at roomtemperature for 72 h and washed with 20% K₂CO₃ (2×25 ml). The aqueouslayer is subjected to extraction with dichloromethane (3×30 ml). Thecombined organic layers are washed with brine (40 ml), dried overNa₂SO₄, and evaporated. The residue (0.55 g) is purified bychromatography on silicagel (chloroform/ethyl acetate 1/1) to afford0.202 g of 1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one 157 (yield0.202 g, 32%).

Yield: 32%.

LC-MS (MH⁺): 209.

Example 79 Synthesis of4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one 241

79.1. Synthesis of5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine x254

The commercially available 5-bromo-1H-pyrrolo[2,3-b]pyridine x253 (0.94g, 4.77 mmol) is dissolved in freshly distilled absolute1,2-dimethoxyethane (15 ml). Then 100% NaH (0.126 g, 1.1 eq, 5.25 mmol,obtained bywashing a 60% NaH emulsion with hexane in a flow of argon) isadded at 0° C. under vigorous stirring. The reaction mixture is takenaway from the cooling bath and stirred for 15 min at room temperature.After this, triisopropylsilyl chloride (1.1 g, 1.2 eq, 5.73 mmol) isadded dropwise, and tetrabutylammonium bromide (0.307 g, 0.2 eq, 0.95mmol) is added. The reaction mixture is stirred for 5 h in a flow ofargon, cooled, and poured into 5% aqueous NaHCO₃ (10 ml). The product isextracted with hexane (2×100 ml). The combined extracts are dried withanhydrous sodium sulfate and evaporated. The residue is purified bychromatography on silicagel (hexane/CCl₄) to afford 1.15 g of5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine x254.

Yield: 70%.

LC-MS (MH⁺): 354.

79.2. Synthesis of1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde x255

Bromide x254 (1.1 g, 3.11 mmol) is dissolved in freshly distilledabsolute THF (40 ml). A 1.7 M solution of t-BuLi in pentane (1.92 ml,1.05 eq) is added dropwise at −100° C. under vigorous stirring in a flowof argon. The reaction mixture is stirred for 45 min and meanwhileallowed to heat up slowly to −78° C. After this, a solution ofN-formylpiperidine (0.42 g, 1.2 eq, 3.73 mmol) in freshly distilledabsolute THF (5 ml) is added dropwise for 5 min. The mixture is allowedto heat up to 0° C. under stirring in the cooling bath, and then pouredinto a mixture of saturated aqueous NH₄Cl (20 ml) and 1:1 hexane/ethermixture (100 ml). The organic phase is separated, dried with anhydroussodium sulfate, and evaporated. The residue is purified bychromatography on silicagel, CCl₄/MeCN) to afford 0.7 g of1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde x255.

Yield: 75%.

LC-MS (MH⁺): 303.

79.3. Synthesis of4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-onex256

Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolvedin absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate(1 g) are added under vigorous stirring. After 15 min, the mixture isdiluted with ether (100 ml) and filtered. The solid on the filter iswashed with ether (2×50 ml). A solution of aldehyde x255 (0.7 g, 1 eq,2.3 mmol) in methanol (5 ml) is added immediately. The combined solutionis evaporated in the vacuum of a rotary evaporator. The residue isdissolved in methanol (10 ml), CH(OMe)₃ (0.5 ml) is added, and theobtained solution is stirred at room temperature for 16 h. An excess ofNaBH₄ (1 g in several small portions) is then added to the reactionsolution under vigorous stirring for 20 min. The reaction mixture isevaporated in the vacuum of a rotary evaporator. The residue ispartitioned between ethyl acetate and water. The organic phase isseparated, dried with anhydrous sodium sulfate, and evaporated. Theresidue is dissolved in acetonitrile (10 ml), and the solution isrefluxed for 24 h to complete the cyclization. The solvent is distilledoff. The residue is purified by chromatography on silicagel (CCl₄/MeCN)to afford4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-onex256.

Yield: 75% (0.72 g).

LC-MS (MH⁺): 414.

79.4. Synthesis of4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one 241.

4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-onex256 (0.7 g, 1.7 mmol) is dissolved in absolute THF (7 ml). A 1 Msolution of tetrabutylammonium fluoride in THF (1.7 M, 1 eq) is added.The obtained solution is stirred for 10 min at room temperature andpoured into a mixture of ether (100 ml) and water (20 ml). The organicphase is separated, dried with anhydrous sodium sulfate, and evaporated.The residue is purified by chromatography on silicagel(dichloromethane/isopropanol) to yield 0.43 g of4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one 241.

Yield: 99%.

LC-MS (MH⁺): 258.

Example 80 Synthesis of4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one 240

80.1. Synthesis of 1H-pyrrolo[2,3-b]pyridine 7-oxide x257.

The commercially available 1H-pyrrolo[2,3-b]pyridine x7 (6.0 g, 50.8mmol) is dissolved in 1,2-dimethoxyethane (50 ml). A solution of 70-75%m-chloroperbenzoic acid (17 g, 1.4 eq, 71.1 mmol) in 1,2-dimethoxyethane(40 ml) is added under cooling with cold water at a temperature below25° C. The obtained suspension of the salt is stirred additionally for 1h, kept overnight at −20° C. and filtered. The solid on the filter iswashed with ether (2×30 ml) and air-dried. The obtained product isdissolved in a minimum of water. The pH of the solution is adjusted to 9by the addition of aqueous K₂CO₃ under stirring and cooling with coldwater. The formed suspension of the free N-oxide x257 is kept at +3° C.overnight and filtered. The product is washed with ice-cold water (2×10ml) and dried over P₂O₅ under 1 mmHg to yield 1H-pyrrolo[2,3-b]pyridine7-oxide x257 (3.4 g).

Yield: 41%.

LC-MS (MH⁺): 135.

80.2 Synthesis of 4-bromo-1H-pyrrolo[2,3-b]pyridine x258

1H-pyrrolo[2,3-b]pyridine 7-oxide x257 (3.4 g, 25.4 mmol) andtetramethylammonium bromide (4.7 g, 1.2 eq, 30.4 mmol) are dissolved inDMF (33 ml). Then Ms₂O (8.8 g, 2 eq, 50.8 mmol) is added at 0° C. insmall portions. The obtained mixture is stirred for 1 h at 0° C., thenfor 4 h at room temperature, and diluted with water (66 ml). The pH isadjusted to 7 with solid NaOH, and 130 ml more of water is added. Theresulting suspension is kept at 5° C. for 1 h. The precipitate isseparated by filtration, washed with ice-cold water (2×10 ml), and driedover P₂O₅ under 1 mmHg. The crude sample of x258 (˜80% pure) is purifiedto the analytically pure state by HPLC to yield 2.2 g of4-bromo-1H-pyrrolo[2,3-b]pyridine x258.

Yield: 45%.

LC-MS (MH⁺): 198.

80.3. Synthesis of4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one 240.

The further transformation of bromide x258 into the target product 240is carried out in complete accordance with the transformation of bromideb191-1 into product ucb-108891-1 as described in examples 79.2 to 79.4.The yields are similar for intermediates4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine x259,1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde x260 and4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methyl}pyrrolidin-2-onex261. As a result, 1.0 g (5.1 mmol) of 4-bromo-1H-pyrrolo[2,3-b]pyridinex258 affords 0.45 g of4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one 240.

Overall yield: 35%.

LC-MS (MH⁺): 258.

Example 81 Synthesis of1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one 264

81.1. Synthesis of 1-(2-fluoroindolizin-3-yl)methanamine x263.

LiAlH₄ (0.175 g, 4.6 mmol) is added in portions under stirring in argonto a solution of 2-fluoroindolizine-3-carbonitrile x262 [X. Fang, Y.-M.Wu, J. Deng, S.-W. Wang, Tetrahedron 2004, 60, 5487-5493] (0.46 g, 2.9mmol) in absolute ether (15 ml) for 3 min. The reaction mixture isstirred at room temperature for 30 min, cooled to 0-5° C., and quenchedby the addition of a 10% NaOH solution (4 ml). The organic layer isseparated, and the aqueous layer is subjected to extraction with ether(3×10 ml). The combined organic extracts are dried over anhydrousNa₂SO₄. The solvents are removed reduced pressure to give1-(2-fluoroindolizin-3-yl)methanamine x263 (0.38 g).

Yield: 85%.

¹H NMR (DMSO-d₆): 1.81 (s broad, 2H), 4.00 (s, 2H), 6.23 (s, 1H), 6.65(t, J=6.85 Hz, 1H), 6.80 (t, J=8.8 Hz, 1H), 7.37 (d, J=8.81 Hz, 1H),8.24 (d, J=8.09 Hz, 1H).

81.2. Synthesis of1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one 264.

A solution of 1-(2-fluoroindolizin-3-yl)methanamine x263 (0.38 g, 2.3mmol) and 5-hydroxy-4-propyldihydrofuran-2(3H)-one x252 (0.33 g, 2.3mmol) in DCE (12 ml) is kept at room temperature for 2 h, then STAB(0.74 g, 3.5 mmol) is added, and the mixture is stirred overnight. Thereaction mixture is kept under stirring at 50° C. for 2 h, cooled toroom temperature, and diluted with dichloromethane (10 ml). The mixtureis washed with a 20% K₂CO₃ solution (2×15 ml), and the aqueous layer iswashed with brine (25 ml), dried over anhydrous Na₂SO₄ and evaporated.The residue (0.60 g) is purified by chromatography on silica gel(gradient: chloroform to chloroform/methanol 50/1) to isolate a productof approximately 80% purity (0.162 g). This product is purified bychromatography on silicagel (hexane/ethyl acetate 5/2) to afford pure1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one 264 (0.126g).

Yield: 20%.

LC-MS (MH⁺): 275.

Example 82 Synthesis of1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one 299

82.1 Synthesis of 4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264

18-Crown-6 (0.158 g, 0.2 eq, 0.6 mmol) is dissolved in absolute ether(20 ml). A 1.7 M solution of potassium tert-amylate in toluene (1.93 ml,1.1 eq, 3.28 mmol) is added dropwise in a flow of argon. The reactionmixture is stirred for 15 min at room temperature. Pyrrole (0.2 g, 1 eq,2.98 mmol) is added. The reaction mixture is cooled to −15° C., and asolution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.603 g, 1.15eq, 3.43 mmol) in absolute ether (5 ml) is added dropwise. The resultingsolution is stirred for 16 h at 20° C. The contents of the flask arepartitioned between 10 ml of water and 30 ml of ethyl acetate. Theorganic layer is separated. The aqueous one is subjected to additionalextraction with ethyl acetate (2×20 ml). The combined extracts are driedwith anhydrous Na₂SO₄ and evaporated. Purification by chromatography onsilicagel (dichloromethane/acetone) afford 0.091 g of4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264.

Yield: 15%.

¹H NMR (CDCl₃): 0.87 (t, J=7.10 Hz, 3H), 1.23-1.40 (m, 4H), 2.06 (dd, J7.0; 16.6 Hz, 1H), 2.30 (hept, J=7.33 Hz, 1H), 2.06 (dd, J 8.5; 16.6 Hz,1H), 2.90 (dd, J 6.8; 9.2 Hz, 1H), 3.40 (dd, J 8.05; 9.2 Hz, 1H), 5.24(d, J=13.7 Hz, 1H), 5.32 (d, J=13.7 Hz, 1H), 6.17 (t, J=2.20 Hz, 2H),6.74 (t, J=2.20 Hz, 2H).

82.2. Synthesis of1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one 299

4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264 (0.182 g, 0.88mmol) is dissolved in absolute THF (3 ml). A solution ofN-chlorosuccinimide (0.118 g, 1 eq) in absolute THF (1 ml) is addeddropwise in a flow of argon at 0° C. The obtained solution is allowed toheat up slowly to room temperature in the cooling bath under stirringfor 16 h. CCl₄ (30 ml) is then added to the obtained solution. A smallamount of a precipitate is filtered off, and the filtrate is evaporated.1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one 299 isisolated from the residue by reverse-phase HPLC (eluent:acetonitrile/water).

Yield: 50% (0.106 g).

LC-MS (MH⁺): 241/243.

1-[(2,5-dichloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one 298 maybe synthesized analogously using 2 eq. of N-chlorosuccinimide.

Yield: 70%.

LC-MS (MH⁺): 275/277/279.

Example 83 Synthesis of1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one90

83.1. Synthesis of2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole x266.

A mixture of bromoacetophenone (0.775 g, 3.895 mmol, 1.1 eq) and5-cyclopropyl-2-amino-thiadiazole x265 (0.5 g, 3.54 mmol, 1 eq) in EtOH(20 ml) are heated in microwave at 120° C. during 5 hours. Water (20 ml)is added then the aqueous layer is extracted with CH₂Cl₂ (3×30 ml). Thecombined organic layers are dried on anhydrous MgSO₄, filtered off andevaporated under reduced pressure to yield pure2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole x266 as a yellowpowder (850 mg,

Yield: 25%.

LC-MS (MH⁺): 242.

83.2. Synthesis of1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one90

1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one90 is synthesized according to the method described in example 66.3,using 2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole x266 asstarting material.

Yield: 38%.

LC-MS (MH⁺): 381.

Example 84 Synthesis of1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one4

To a refluxing solution of acetic acid (8 ml) and sulfuric acid (2drops) is added, dropwised, a solution of1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (400 mg, 2.54 mmol) in 3ml of acetic acid. 6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridinex267 (309 mg, 1.27 mmol, 0.5 eq) is then added in once. The reactionmixture is refluxed for 3 days. After cooling, the reaction mixture isslowly poored in 150 ml of concentrated sodium hydroxyde solution (40%wt) and the crude product is extracted by dichloromethane (4×150 ml).The cumulated organic layers are dried over MgSO₄, filtered andcondensed under reduced pressure leading to the crude product which ispurified by flash chromatography over silicagel (hexane/ethyl acetate80/20).1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one4 is recrystallized in ethyl acetate.

Yield: 9%.

LC-MS (MH⁺): 382/384.

Example 85 Synthesis of1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one45

A solution of1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one30 (500 mg, 1.38 mmol), sodium hydroxide (110 mg, 2.77 mmol, 2 eq) in 5ml of a 1/1 mixture of acetonitrile and water is heated in a microwaveoven for 20 min (T_(max) 150° C.). Acetonitrile is removed from reactionmixture under reduced pressure, the aqueous layer is acidified usingaqueous hydrochloric acid solution and the crude product is thenextracted by ethyl acetate (3×20 ml). The cumulated organic layers aredried over MgSO₄, filtered and condensed under reduced pressure leadingto an oily residue which is purified by preparative chromatography onsilicagel (dichloromethane/isopropanol 99/1). The resulting solid isdried in a vacuum oven and recrystallized in ethyl acetate to afford1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one45.

Yield: 10%.

LC-MS (MH⁺): 343.

Example 86 Synthesis of1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one53

86.1. Synthesis of1-{[6-[(2,4-dimethoxybenzyl)amino]-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-onex268

1-{[6-[(2,4-dimethoxybenzyl)amino]-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-onex268 is prepared according to the method described in example 39.

LC-MS (MH⁺): 492.

86.2. Synthesis of1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one53

1-{[6-[(2,4-dimethoxybenzyl)amino]-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-onex268 (396 mg, 0.83 mmol) is stirred at room temperature intrifluoroacetic acid until its complete consumption (17 hours). AfterTFA removal under reduced pressure, the residue is taken in saturatedK₂CO₃ aqueous solution and extracted with ethyl acetate (3×15 ml). Thecumulated organic layers are dried over MgSO₄, filtered and condensedunder reduced pressure to yield the crude material which is purified byreverse phase preparative chromatography (gradientacetonitrile/water/TFA) to afford1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one53.

Yield: 11%.

LC-MS (MH⁺): 342.

Example 87 Synthesis of4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2-(trifluoromethyl)-imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one56

4-(2,2-difluorovinyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-pyrrolidin-2-one57 (178 mg, 0.44 mmol) is dissolved in an aqueous solution of bromhydricacid (62% wt, 5 ml). The resulting solution is kept under agitation for17 hours at room temperature. After neutralization until alkaline pHwith saturated K₂CO₃ aqueous solution, the title compound is isolatedafter extraction with dichloromethane (3×15 ml), drying of the cumulatedorganic layers over MgSO₄, filtration and evaporation of the solventunder reduced pressure. The resulting product is re-crystallized inethyl acetate to afford4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one56.

Yield: 69%.

LC-MS (MH⁺): 484/486.

Example 88 Synthesis of4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one64 and4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one67

A mixture of1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one33 (500 mg, 1.31 mmol), palladium on charcoal (10% wt, 50 mg) in 20 mlof ethanol, is hydrogenated (5 bars of H₂) during 17 hours. Afterfiltration over celite of the catalyst and solvent evaporation, the twotitle compounds are purified and separated by preparative chromatographyon silicagel (CH₂Cl₂/MeOH/NH₄OH: 99/1/0.1). Both compounds arerecrystallized in ethyl acetate.

4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one64:

Yield: 24%.

LC-MS (MH⁺): 347.

4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one67:

Yield: 16%.

LC-MS (MH⁺): 349.

Example 89 Synthesis of1-{[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-propylpyrrolidin-2-one87

To a solution of1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one30 (72 mg, 0.2 mmol) in methanol (1 ml) is added dropwised sodiumborohydride (15 mg, 2 eq, 0.4 mmol). The resulting mixture is stirred atroom temperature for 3 days, afterwards a small amount of sodiumborohydride is added to complete the reaction. After 17 hours ofagitation at room temperature, water (2 ml) is added and methanol isremoved under reduced pressure. Addition of 2 ml of saturated aqueoussolution of NH₄Cl is followed by extraction with ethyl acetate (3×5 ml).Drying of the cumulated organic layers over MgSO₄, filtration andevaporation afford the crude product which is purified by reverse phasepreparative chromatography over silicagel (gradientacetonitrile/water/TFA) to yield1-{[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-propylpyrrolidin-2-one87.

Yield: 72%.

LC-MS (MH⁺): 331.

Example 90 Synthesis of4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one 242

Potassium terbutoxide (522 mg, 4.65 mmol, 1.1 eq) is added to a solutionof 6-azaindole x269 (500 mg, 4.23 mmol) in 4 ml of THF at 0° C. After 1hour of reaction at 0° C., a freshly prepared solution of4-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.814 mg, 4.65 mmol, 1.1eq, in 3 ml of THF) at 0° C. The reaction mixture is warmed to roomtemperature. After 3 days of agitation, water (10 ml) is added and theaqueous layer is washed with ethyl acetate (3×15 ml). The aqueous layeris then neutralized until pH 9 and extracted with dichloromethane (3×15ml). The cumulated dichloromethane layers are dried over MgSO₄,filtrated and condensed under reduced pressure. The resulting residue ispurified by preparative chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH96/4/0.4 (v/v/v)), recrystallized in ethyl acetate, leading to4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one 242 asa solid.

Yield: 7.5%.

LC-MS (MH⁺): 258.

Example 91 Synthesis of1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one219

91.1. Synthesis of 5,7-dichloro-2-cyclopropylpyrazolo[1,5-a]pyrimidinex272.

A sodium ethoxide solution (EtOH/EtONa, 0.5 N, 400 ml) containingdiethyl malonate (50 mmol, 1 eq., 5.8 ml, 6.6 g) and5-cyclopropyl-1H-pyrazol-3-amine (50 mmol, 1 eq., 6.16 g) is refluxedfor 7 hours. After cooling to room temperature, an aqueous hydrochloricacid solution (5 N, 240 ml) is added until pH 5 is obtained. Volatilesare then removed under reduce pressure and the residue dried undervacuum to afford2-cyclopropyl-7-hydroxypyrazolo[1,5-a]pyrimidin-5(4H)-one x271. To thisresidue is successively added POCl₃ (125 ml, 1.34 mol) andN,N-dimethylaniline (12.5 ml, 0.1 mol, 2 eq.) and the resulting mixtureis refluxed during 3 hours. After cooling to room temperature, thereaction mixture is poured on ice and stirred during one hour at thistemperature. The reaction mixture is extracted with dichloromethane, andthe resulting organic phase is washed twice with water. The organicphase is dried over Na₂SO₄, filtered and evaporated under reducepressure. The crude product is purified chromatography on silicagel(CH₂Cl₂/hexane: 40/60) to afford 5.85 g of5,7-dichloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x272 as a solid.

Yield: 52%.

LC-MS (MH⁺): 228/230/232.

5,7-dichloro-2-cyclopropyl-6-methylpyrazolo[1,5-a]pyrimidine x273 (LC-MS(MH⁺): 242/244/246) may be synthesized according to the same method.

91.2. Synthesis of 5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x274.

To a solution of 5,7-dichloro-2-cyclopropylpyrazolo[1,5-a]pyrimidinex272 (26.7 mmol, 1 eq., 6.08 g) in 125 ml of AcOH is added Zn powder(0.107 mol, 4 eq, 6.97 g). The mixture is then stirred for 48 hours atroom temperature. After this time, the solvent is evaporated underreduce pressure and the reaction mixture poured on water, quenched withNaHCO₃, and extracted with dichloromethane. The organic layer is driedover Na₂SO₄, filtered and evaporated under reduced pressure. The crudeproduct is purified by chromatography on silicagel (CH₂Cl₂/hexane:50/50) to afford 5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x274 asa solid (3.60 g).

Yield: 70%.

LC-MS (MH⁺): 194/196.

5-chloro-2-cyclopropyl-6-methylpyrazolo[1,5-a]pyrimidine x275 (LC-MS(MH⁺): 208/210) may be synthesized according to the same method.

91.3. Synthesis of1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one219

To a solution of 1-(chloromethyl)-4-(2,2-difluorovinyl)pyrrolidin-2-onex276 (2.55 mmol, 2 eq, 500 mg) in 15 ml of dioxane at 0° C. are addedsuccessively AlCl₃ (5.1 mmol, 2 eq, 680 mg) and5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x274 (2.55 mmol, 1 eq,495 mg). The mixture is stirred at reflux for 1 hour, then quenched withan aqueous saturated NH₄Cl solution and the resulting mixture extractedwith AcOEt. The cumulated organic layers are washed with water, driedover MgSO₄, filtered and evaporated under reduced pressure. The crudeproduct is purified by chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH:98/2/0.2), followed by a crystallization step in hexane.1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one219 is obtained as a solid (623 mg).

Yield: 69%.

LC-MS (MH⁺): 353/355.

Compound 220 may be prepared according to the same method.

Example 92 Synthesis of benzyl1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-2-ylcarbamate130

92.1. Synthesis of1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylicacid x277

In a Parr pressure bottle, compound 125 (1.8 g, 7.34 mmol) is dissolvedin 80 ml of HCl (18% w/w) and the reaction is heated overnight at 100°C. Another portion of HCl (37% w/w, 10 ml) is added and heating isrestarted for 6 h at 100° C. The mixture is cooled down to 20° C.overnight, evaporated to dryness and dried by azeotropic distillationwith toluene to afford1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylicacid x277 (2.3 g, quantitative) which is used in the next step withoutany further purification.

92.2. Synthesis of benzyl1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-2-ylcarbamate130

In a two neck flas, fitted with a reflux condenser, under argon,diphenylphosphoryl azide (0.37 g) is added to1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylicacid x277 (1 g, 3.33 mmol, carefully dried by azeotropic distillationwith toluene) dissolved in toluene (dried on Na) at room temperature,followed by Et₃N (0.7 ml). The reaction mixture is stirred overnight atroom temperature. Benzyl alcohol (0.69 ml) is added and the reactionmixture is heated rapidly at 90° C. for one hour, cooled down to roomtemperature and evaporated to dryness. The solid residue is diluted inDCM, washed with aqueous NaHCO₃, and the organic layer is dried withMgSO₄, filtered and concentrated in vacuo. The reaction mixture ispurified several times by column chromatography on silicagel(CH₂Cl₂/MTBE/MeOH/NH₄OH 50/48/1.98/0.2) to afford benzyl1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-2-ylcarbamate130 (0.04 g).

Yield: 3.2%.

LC-MS (MH⁺): 371.

Example 93 Synthesis of1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one178

93.1 Synthesis of ethyl3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoate x279

In a three neck flask, fitted with a reflux condenser, under argon, asolution of ethyl 3-(aminomethyl)hexanoate (11.8 g, 0.042 mol) in EtOH(50 ml) is added via a pump-syringe (5 ml/h) onto a solution of ethyl2-(hydroxymethyl)acrylate x278 (5 g, 0.038 mol) and Et₃N (8.03 ml) inTHF (100 ml) at room temperature. After 6 h, the reaction mixture isfiltered on celite, washed with saturated NaHCO₃ and the aqueous layeris extracted with CH₂Cl₂ (2×150 ml), dried with MgSO₄, filtered andconcentrated in vacuo. The crude reaction mixture is purified bychromatography on silicagel (CH₂Cl₂/MTBE/MeOH 50/49/1), to afford 3.7 gof ethyl 3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoatec279.

Yield: 37%.

LC-MS (MH⁺): 258.

93.2. Synthesis of ethyl2-formyl-3-(2-oxo-4-propylpyrrolidin-1-yl)propanoate x280

In a three neck flask, fitted with a magnetic stirrer, under inertatmosphere, DMSO (dried on CaH₂, 0.83 g, 0.01 mol) in CH₂Cl₂ (5 ml) isadded onto a solution of (COCl)₂ (0.72 g, 0.0052 mol) in CH₂Cl₂ (5 ml)cooled at −78° C. After 0.5 h at −78° C., ethyl3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoate x279 (0.92g, 0.0035 mol) in CH₂Cl₂ (10 ml) is added, stirred for 2.5 h at −60° C.,quenched with Et₃N (2.75 ml), stirred overnight at 4° C., washed withsaturated NH₄Cl and extracted 3 times with CH₂Cl₂. The combined organicphases are dried over MgSO₄, filtered, concentrated in vacuo to give thecrude x280 (1.2 g) which is used in the next step without any furtherpurification.

LC-MS (MH⁺): 256.

93.3. Synthesis of2-benzyl-4-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2,4-dihydro-3H-pyrazol-3-onex281

In a three neck flask, fitted with a magnetic stirrer, under inertatmosphere, ethyl 2-formyl-3-(2-oxo-4-propylpyrrolidin-1-yl)propanoatex280 (0.9 g) in PhMe (10 ml) is added onto a solution of Et₃N (1.6 ml)and PhCH₂NHNH₂O.2HCl (0.75 g, 0.0039 mol.) in PhMe (30 ml) at roomtemperature. The mixture is heated up to 40° C. for 12 h, cooled down toroom temperature, washed with NH₄Cl (saturated) and the aqueous layer isacidified to pH 3 by addition of HCl (5 N). After 3 extractions withEtOAc, the organic layers are dried over MgSO₄, concentrated in vacuo toafford the crude reaction mixture which is purified by chromatography onsilicagel (first purification with CH₂Cl₂/MeOH/NH₄OH 98/018/0.02; secondpurification with EtOAC/iPrOH 95/5; third purification by preparativereverse phase LC/MS) to afford2-benzyl-4-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2,4-dihydro-3H-pyrazol-3-onex281 as a red oil (0.18 g).

Yield: 14%.

LC-MS (MH⁺): 314.

93.4. Synthesis of1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one178

In a three neck flask, fitted with a magnetic stirrer, under inertatmosphere, a mixture of POCl₃ (0.13 g, 0.9 mmol),2-benzyl-4-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2,4-dihydro-3H-pyrazol-3-onex281 (0.18 g, 0.43 mmol) and PhMe (4 ml) is heated at 95° C. for 2 h,cooled down to room temperature overnight and quenched with saturatedNaHCO₃. The aqueous layer is extracted 3 times with CH₂Cl₂, combinedorganic phases are dried over MgSO₄, filtered and concentrated in vacuoto afford the crude chloride which is purified by column chromatographyon silicagel (CH₂Cl₂/MeOH/NH₄OH: 8/4/0.04 (v/v/v)) followed by a secondpurification by preparative HPLC to afford 0.036 g of1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one178 as a solid.

LC-MS (MH⁺): 332/334.

Example 94 Synthesis of1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 230

To a solution of 2-aminonicotinaldehyde x282 (8.19 mmol, 1 eq, 1 g) in10 ml of EtOH, is added ethyl 3-(aminomethyl)hexanoate hydrochloride x31(9.83 mmol, 1.2 eq, 2.06 g) and the resulting solution is stirred atroom temperature for 1 h30. Then, triethylamine (9.0 mmol, 1.1 eq, 909mg) is added and the mixture is stirred during 0.5 hour. Sodiumborohydride is then added (9.83 mmol, 1.2 eq, 372 mg). The resultingmixture is stirred at room temperature for 20 hours, heated at 55° C.for 21 hours and then overnight at room temperature. Volatiles areremoved under vacuum and CH₂Cl₂ (50 ml) and water (25 ml) are added. Theorganic layer is washed with water (25 ml) and dried over MgSO₄. Afterfiltration, volatiles are removed under reduced pressure. The crudeproduct is purified by chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH98/2/0.2 (v/v/v)) and recrystallized in AcOEt to afford1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 230 as a whitesolid (152 mg).

Yield: 8%.

LC-MS (MH⁺): 234.

Table I indicates the stereochemical information in the columns headed“configuration”: the first one indicates whether a compound has nostereogenic center (achiral), is a pure enantiomer (pure), a racemate oris a mixture of two stereoisomers, possibly in unequal proportions(mixture); the second one contains the stereochemical assignment for therecognised center, following the IUPAC numbering used in the “IUPACname” column. A number alone indicates the existence of bothconfigurations at that center. A number followed by ‘R’ or ‘S’ indicatesthe known absolute configuration at that center. A number followed by‘§’ indicates the existence of only one but unknown absoluteconfiguration at that center. The letter (A, B) in front is a way ofdistinguishing the various enantiomers of the same structure. Table 1indicates also the type of salt, which is synthesized (if not the freebase), the IUPAC name of the compound, the ion peak observed in massspectroscopy and the optical rotation in the case of chiral compounds.

TABLE 1 ¹H NMR delta (CDCl₃ unless otherwise n^(o) Config Salt IUPACName MH⁺ (M⁺.) specified) 1 4 1-[(1-methyl-1H-benzimidazol-6- 272(DMSO): 0.83 (t, 7.16 Hz, 3H), 1.15-1.39 (m,yl)methyl]-4-propylpyrrolidin-2-one 4H), 2.00 (dd, 16.31, 7.53 Hz, 1H),2.25 (m, 1H), 2.44 (dd, 16.31, 8.53 Hz, 1H), 2.86 (m, 1H), 3.35 (m, 1H),3.82 (s, 3H), 4.47 (s, 2H), 7.07 (d, 8.04 Hz, 1H), 7.40 (s, 1H), 7.60(d, 8.04 Hz, 1H), 8.16 (s, 1H) 2 4 1-(1H-benzimidazol-7-ylmethyl)-4- 2580.89 (t, J 7.18 Hz, 3H), 1.23-1.32 (m, 2H), propylpyrrolidin-2-one1.34-1.40 (m, 2H), 2.14 (dd, J 16.87, 7.81 Hz, 1H), 2.34 (m, 1H), 2.59(dd, J 16.87, 8.81 Hz, 1H), 3.04 (dd, J 9.82, 6.92 Hz, 1H), 3.51 (dd, J9.57, 8.31 Hz, 1H), 4.59 (d, J 17.60 Hz, 1H), 4.64 (d, J 17.60 Hz, 1H),7.12 (d, J 7.05 Hz, 1H), 7.22 (t, J 7.31 Hz, 1H), 7.81 (d, J 8.06 Hz,1H), 8.04 (s, 1H), 11.14 (s (broad), 1H) 3 4 1 CF₃COOH1-(imidazo[1,2-a]pyridin-3-ylmethyl)- 258 0.82 (m, 3H), 1.24 (m, 4H),2.01 (dd, 25.62, 4-propylpyrrolidin-2-one 12.32 Hz, 1H), 2.26 (m, 1H),2.42 (d, 25.86 Hz, 1H), 2.92 (dd, 14.64, 10.86 Hz, 1H), 3.40 (m, 1H),4.84 (m, 3H), 7.58 (td, 10.25, 3.23 Hz, 1H), 7.99 (m, 2H), 8.23 (s, 1H),8.75 (d, 10.74 Hz, 1H) 4 4 1-{[6-chloro-2-(4- 382/384 0.82 (t, 7.04 Hz,3H), 1.23 (m, 4H), 2.09 (m, methylphenyl)imidazo[1,2-a]pyridin- 1H),2.21 (m, 1H), 2.42 (s Hz, 3H), 3-yl]methyl}-4-propylpyrrolidin-2-one2.56 (dd, 16.60, 8.30 Hz, 1H), 2.71 (dd, 9.05, 6.92 Hz, 1H), 3.18 (m,1H), 4.94 (m, 2H), 7.20 (d, 9.56 Hz, 1H), 7.28 (m, 2H), 7.60 (m, 3H),8.43 (s, 1H) 5 4 1-{[2-(4-chlorophenyl)-6- 382/384 0.81 (m, 3H), 1.21(m, 4H), 2.09 (m, 1H), methylimidazo[1,2-a]pyridin-3- 2.19 (m, 1H), 2.35(s, 3H), 2.55 (dd, 16.60, yl]methyl}-4-propylpyrrolidin-2-one 8.30 Hz,1H), 2.68 (m, 1H), 3.15 (t, 8.68 Hz, 1H), 4.93 (m, 2H), 7.12 (d, 9.05Hz, 1H), 7.27 (d, 0.75 Hz, 1H), 7.45 (d, 7.55 Hz, 2H), 7.55 (d, 9.31 Hz,1H), 7.69 (d, 7.29 Hz, 2H), 8.08 (s, 1H) 6 4 1 CF₃COOH1-[(5-methylimidazo[1,2-a]pyridin-3- 306 2.69 (m, 1H), 2.90 (m, 1H),2.96 (s, 3H), yl)methyl]-4-phenylpyrrolidin-2-one 3.30 (m, 1H), 3.65 (m,2H), 4.87 (dd, 16.10, 3.65 Hz, 1H), 5.28 (dd, 16.10, 3.77 Hz, 1H), 6.99(m, 1H), 7.16 (m, 2H), 7.29 (m, 4H), 7.58 (m, 1H), 7.78 (d, 4.02 Hz,1H), 8.11 (dd, 8.55, 3.40 Hz, 1H) 7 4 1 CF₃COOH1-(imidazo[1,2-a]pyridin-3-ylmethyl)- 292 2.64 (m, 1H), 2.82 (m, 2H),3.33 (dd, 14.64, 4-phenylpyrrolidin-2-one 10.98 Hz, 1H), 3.56 (m, 1H),3.71 (m, 1H), 4.90 (m, 2H), 7.09 (m, 2H), 7.29 (m, 4H), 7.75 (m, 1H),7.89 (s, 1H), 8.28 (m, 1H), 8.84 (d, 10.98 Hz, 1H) 8 4 1 HCl1-[(6-methylimidazo[1,2-a]pyridin-3- 272 0.87 (m, 3H), 1.30 (m, 4H),2.11 (m, 1H), yl)methyl]-4-propylpyrrolidin-2-one 2.32 (m, 1H), 2.57 (m,4H), 2.96 (t, 6.67 Hz, 1H), 3.46 (m, 1H), 4.85 (m, 2H), 7.16 (m, 1H),8.02 (d, 44.52 Hz, 2H), 8.73 (m, 1H) 9 4 1 HCl1-[(6-bromoimidazo[1,2-a]pyridin-3- 336 0.89 (t, 7.17 Hz, 3H), 1.34 (m,4H), yl)methyl]-4-propylpyrrolidin-2-one 2.14 (dd, 16.85, 8.05 Hz, 1H),2.37 (m, 1H), 2.60 (dd, 17.10, 8.68 Hz, 1H), 3.00 (dd, 8.80, 7.42 Hz,1H), 3.49 (t, 8.80 Hz, 1H), 4.85 (m, 2H), 7.89 (d, 9.56 Hz, 1H), 8.10(s, 1H), 8.24 (d, 9.56 Hz, 1H), 9.19 (s, 1H) 10 4 1 HCl1-[(8-methylimidazo[1,2-a]pyridin-3- 272 0.87 (t, 11.10 Hz, 3H), 1.31(m, 4H), yl)methyl]-4-propylpyrrolidin-2-one 2.11 (m, 1H), 2.32 (m, 1H),2.57 (m, 1H), 2.97 (m, 4H), 3.49 (m, 1H), 4.92 (m, 2H), 7.27 (m, 1H),7.58 (d, 11.47 Hz, 1H), 8.26 (s, 1H), 8.73 (d, 10.74 Hz, 1H) 11 4 1 HCl1-[(6-iodoimidazo[1,2-a]pyridin-3- 384 0.89 (m, 3H), 1.32 (m, 4H), 2.14(dd, 26.60, yl)methyl]-4-propylpyrrolidin-2-one 12.57 Hz, 1H), 2.36 (m,1H), 2.60 (m, 1H), 2.99 (dd, 15.37, 11.10 Hz, 1H), 3.48 (m, 1H), 4.83(m, 2H), 8.01 (m, 2H), 8.11 (dd, 15.13, 1.22 Hz, 1H), 9.26 (s, 1H) 12 41 CF₃COOH 1-{[8-chloro-6- 360/362 0.87 (t, 11.22 Hz, 3H), 1.30 (m, 4H),(trifluoromethyl)imidazo[1,2- 2.13 (m, 1H), 2.33 (m, 1H), 2.59 (m, 1H),a]pyridin-3-yl]methyl}-4- 2.94 (dd, 15.13, 10.98 Hz, 1H), 3.42 (m, 1H),propylpyrrolidin-2-one 4.79 (m, 2H), 7.56 (d, 2.20 Hz, 1H), 7.88 (s,1H), 9.08 (m, 1H) 13 4 1 HCl 1-[(7-methylimidazo[1,2-a]pyridin-3- 2720.88 (t, 11.22 Hz, 3H), 1.31 (m, 4H),yl)methyl]-4-propylpyrrolidin-2-one 2.16 (m, 1H), 2.34 (m, 1H), 2.57 (m,4H), 2.97 (dd, 14.88, 11.10 Hz, 1H), 3.46 (m, 1H), 4.85 (m, 2H), 7.67(dd, 14.64, 1.83 Hz, 1H), 8.01 (s, 1H), 8.18 (d, 14.88 Hz, 1H), 8.85 (s,1H) 14 4 1 HCl 1-[(6,8-dibromoimidazo[1,2- 414/416/418 0.88 (t, 7.04 Hz,3H), 1.33 (m, 4H), a]pyridin-3-yl)methyl]-4- 2.11 (dd, 16.85, 8.30 Hz,1H), 2.35 (m, 1H), propylpyrrolidin-2-one 2.57 (dd, 16.85, 8.80 Hz, 1H),3.09 (m, 1H), 3.62 (m, 1H), 5.00 (m, 2H), 8.06 (s, 1H), 8.78 (s, 1H),9.30 (s, 1H) 15 4 1 HCl 1-[(6,8-dichloroimidazo[1,2- 326/328/330 0.88(t, 7.04 Hz, 3H), 1.33 (m, 4H), a]pyridin-3-yl)methyl]-4- 2.12 (dd,17.10, 8.17 Hz, 1H), 2.35 (m, 1H), propylpyrrolidin-2-one 2.57 (dd,16.85, 8.55 Hz, 1H), 3.09 (m, 1H), 3.62 (m, 1H), 4.99 (d, 27.92 Hz, 2H),7.79 (s, 1H), 8.75 (s, 1H), 9.15 (s, 1H) 16 41-[(6-chloroimidazo[1,2-a]pyridin-3- 292/294 0.86 (t, 7.17 Hz, 3H), 1.29(m, 4H), yl)methyl]-4-propylpyrrolidin-2-one 2.12 (dd, 16.60, 8.05 Hz,1H), 2.29 (m, 1H), 2.58 (dd, 16.85, 8.68 Hz, 1H), 2.86 (dd, 9.56, 6.79Hz, 1H), 3.34 (dd, 9.56, 8.17 Hz, 1H), 4.73 (m, 2H), 7.19 (dd, 9.56,2.01 Hz, 1H), 7.57 (m, 2H), 8.50 (m, 1H) 17 41-[(2-chloroimidazo[1,2-a]pyridin-3- 292/294 0.86 (t, 7.14 Hz, 3H), 1.29(m, 4H), 2.08 (m, yl)methyl]-4-propylpyrrolidin-2-one 1H), 2.27 (m, 1H),2.53 (dd, 16.85, 8.70 Hz, 1H), 2.93 (m, 1H), 3.44 (m, 1H), 4.77 (m, 2H),6.89 (t, 6.78 Hz, 1H), 7.29 (m, 1H), 7.54 (d, 8.98 Hz, 1H), 8.42 (d,6.96 Hz, 1H) 18 4 1-[(2-cyclopropyl-6- 336 1.24 (m, 2H), 1.36 (m, 2H),2.04 (m, 1H), fluoroimidazo[1,2-a]pyridin-3- 2.29 (m, 1H), 2.71 (dd,17.07, 8.66 Hz, 1H), yl)methyl]-4-(2,2- 3.18 (m, 2H), 3.53 (m, 1H), 4.19(m, 1H), difluorovinyl)pyrrolidin-2-one 4.84 (m, 2H), 7.51 (m, 1H), 8.24(m, 1H), 8.73 (s Hz, 1H) 19 4 1-[(6-chloro-2- 352/354 (DMSO): 0.94 (m,4H), 2.21 (m, 2H), cyclopropylimidazo[1,2-a]pyridin-3- 2.5 (m, 1H),2.98-3.13 (m, 2H), 3.46 (t, 8.16 Hz, yl)methyl]-4-(2,2- 1H), 4.63 (m,1H), 4.82 (s Hz, 2H), difluorovinyl)pyrrolidin-2-one 7.24 (dd, 9.54,1.76 Hz, 1H), 7.48 (d, 9.54 Hz, 1H), 8.56 (d, 1.25 Hz, 1H) 20 4 1CF₃COOH 1-(imidazo[1,2-a]pyrimidin-3- 259 0.82 (m, 3H), 1.24 (m, 4H),1.99 (dd, 25.62, ylmethyl)-4-propylpyrrolidin-2-one 12.32 Hz, 1H), 2.25(m, 1H), 2.42 (m, 1H), 2.92 (dd, 14.64, 11.10 Hz, 1H), 3.39 (m, 1H),4.83 (m, 2H), 7.61 (dd, 10.98, 6.95 Hz, 1H), 8.19 (s, 1H), 8.96 (dd,6.83, 2.56 Hz, 1H), 9.08 (dd, 10.98, 2.56 Hz, 1H) 21 41-{[2-(4-chlorophenyl)imidazo[1,2- 369/371 0.82 (m, 3H), 1.22 (m, 4H),2.08 (dd, 16.85, a]pyrimidin-3-yl]methyl}-4- 7.80 Hz, 1H), 2.21 (m, 1H),2.54 (dd, 16.85, propylpyrrolidin-2-one 8.43 Hz, 1H), 2.75 (m, 1H), 3.22(t, 8.68 Hz, 1H), 4.96 (m, 2H), 6.92 (dd, 5.53, 4.28 Hz, 1H), 7.48 (d,7.55 Hz, 2H), 7.78 (d, 7.55 Hz, 2H), 8.61 (m, 1H), 8.79 (d, 6.79 Hz, 1H)22 4 1-(imidazo[1,2-a]pyrimidin-3- 293 2.46 (dd, 26.35, 13.66 Hz, 1H),2.92 (dd, ylmethyl)-4-phenylpyrrolidin-2-one 14.64, 10.74 Hz, 1H), 3.24(m, 1H), 3.46 (m, 1H), 4.53 (s, 2H), 6.90 (m, 6H), 7.47 (s, 1H), 8.29(dd, 6.59, 3.17 Hz, 1H), 8.57 (dd, 10.98, 3.17 Hz, 1H) 23 41-[(6-chloroimidazo[1,2-a]pyrimidin- 293/295 0.87 (t, 7.17 Hz, 3H), 1.31(m, 4H), 3-yl)methyl]-4-propylpyrrolidin-2-one 2.11 (dd, 16.85, 8.05 Hz,1H), 2.31 (m, 1H), 2.57 (dd, 16.85, 8.55 Hz, 1H), 2.93 (dd, 9.56, 7.04Hz, 1H), 3.40 (m, 1H), 4.71 (m, 2H), 7.77 (s, 1H), 8.50 (d, 2.52 Hz,1H), 8.99 (d, 2.52 Hz, 1H) 24 4 1-{[6-chloro-2- 361/363 0.89 (t, 7.20Hz, 3H), 1.33 (m, 4H), (trifluoromethyl)imidazo[1,2- 2.11 (dd, 16.92,8.08 Hz, 1H), 2.33 (m, 1H), a]pyrimidin-3-yl]methyl}-4- 2.57 (dd, 16.92,8.59 Hz, 1H), 2.98 (dd, 9.60, propylpyrrolidin-2-one 7.07 Hz, 1H), 3.46(m, 1H), 4.85 (m, 2H), 8.63 (d, 2.53 Hz, 1H), 9.25 (d, 2.53 Hz, 1H) 25 41-[(6-phenylimidazo[1,2- 336 0.81 (m, 3H), 1.19 (m, 4H), 2.03 (m, 1H),b][1,2,4]triazin-7-yl)methyl]-4- 2.15 (d, 7.55 Hz, 1H), 2.51 (dd, 16.62,8.44 Hz, propylpyrrolidin-2-one 1H), 2.74 (dd, 9.32, 6.67 Hz, 1H), 3.21(m, 1H), 5.16 (m, 2H), 7.45 (m, 1H), 7.49 (m, 2H), 7.97 (d, 7.05 Hz,2H), 8.41 (d, 2.01 Hz, 1H), 8.49 (d, 2.01 Hz, 1H) 26 41-{[6-chloro-2-(4- 383/385 0.84 (m, 3H), 1.24 (m, 4H), 1.56 (s, 3H),methylphenyl)imidazo[1,2- 2.04 (m, 1H), 2.19 (dd, J = 3.27, 3.27, 2.01,b]pyridazin-3-yl]methyl}-4- 0.88 Hz, 1H), 2.50 (m, 1H), 2.85 (dd, 9.31,propylpyrrolidin-2-one 6.92 Hz, 1H), 3.32 (m, 1H), 5.07 (d, 1.76 Hz,2H), 7.12 (d, 9.31 Hz, 1H), 7.46 (d, 8.30 Hz, 2H), 7.87 (d, 8.55 Hz,2H), 7.93 (d, 9.56 Hz, 1H) 27 4 1-{[6-chloro-2-(4- 403/405/407 0.84 (m,3H), 1.23 (m, 4H), 2.04 (m, 1H), chlorophenyl)imidazo[1,2- 2.20 (m, 1H),2.50 (m, 1H), 2.85 (m, 1H), b]pyridazin-3-yl]methyl}-4- 3.33 (m, 1H),5.08 (s, 2H), 7.12 (dd, 9.31, propylpyrrolidin-2-one 2.01 Hz, 1H), 7.46(dd, 8.30, 1.63 Hz, 2H), 7.87 (dd, 8.30, 1.51 Hz, 2H), 7.93 (dd, 9.31,1.89 Hz, 1H) 28 4 1-[(6-chloroimidazo[1,2-b]pyridazin- 293/295 0.89 (m,3H), 1.33 (m, 4H), 2.09 (dd, 16.35,3-yl)methyl]-4-propylpyrrolidin-2-one 7.67 Hz, 1H), 2.33 (m, 1H), 2.55(dd, 16.35, 8.68 Hz, 1H), 3.01 (m, 1H), 3.50 (m, 1H), 4.85 (s, 2H), 7.07(dd, 9.56, 1.26 Hz, 1H), 7.75 (s, 1H), 7.91 (dd, 9.56, 1.26 Hz, 1H) 29 41-[(6-chloroimidazo[1,2-b]pyridazin- 327/329 2.60 (dd, 17.10, 8.17 Hz,1H), 2.86 (dd, 3-yl)methyl]-4-phenylpyrrolidin-2- 17.10, 8.93 Hz, 1H),3.38 (m, 1H), 3.57 (m, one 1H), 3.79 (m, 1H), 4.93 (m, 2H), 7.07 (d,9.31 Hz, 1H), 7.17 (d, 7.55 Hz, 2H), 7.31 (m, 4H), 7.79 (s, 1H), 7.91(m, 1H) 30 4 1-{[6-chloro-2- 361/363 0.87 (t, 7.17 Hz, 3H), 1.30 (m,4H), (trifluoromethyl)imidazo[1,2- 2.09 (dd, 16.60, 7.80 Hz, 1H), 2.29(m, 1H), b]pyridazin-3-yl]methyl}-4- 2.54 (dd, 16.85, 8.68 Hz, 1H), 2.84(dd, 9.05, propylpyrrolidin-2-one 6.79 Hz, 1H), 3.32 (m, 1H), 5.01 (m,2H), 7.25 (m, 1H), 8.00 (d, 9.56 Hz, 1H) 31 4 1-{[6-chloro-2- 449/4512.57 (dd, 17.10, 7.55 Hz, 1H), 2.87 (dd, (trifluoromethyl)imidazo[1,2-17.10, 9.05 Hz, 1H), 3.21 (dd, 9.56, 6.29 Hz,b]pyridazin-3-yl]methyl}-4-(2,3,5- 1H), 3.69 (t, 8.93 Hz, 1H), 3.82 (m,1H), trifluorophenyl)pyrrolidin-2-one 5.09 (m, 2H), 6.62 (m, 1H), 6.81(m, 1H), 7.28 (m, 1H), 8.00 (d, 9.56 Hz, 1H) 32 1-{[6-chloro-2- 319/3211.97 (m, 2H), 2.39 (t, 8.05 Hz, 2H), 3.24 (t,(trifluoromethyl)imidazo[1,2- 7.04 Hz, 2H), 5.02 (s, 2H), 7.20 (d, 9.56Hz, b]pyridazin-3-yl]methyl}pyrrolidin-2- 1H), 7.96 (d, 9.56 Hz, 1H) one33 4 1-{[6-chloro-2- 381/383 2.23 (dd, 16.83, 8.04 Hz, 1H), 2.66 (dd,(trifluoromethyl)imidazo[1,2- 16.83, 8.79 Hz, 1H), 2.98 (dd, 9.04, 7.28Hz, b]pyridazin-3-yl]methyl}-4-(2,2- 1H), 3.12 (m, 1H), 3.44 (t, 8.67Hz, 1H), difluorovinyl)pyrrolidin-2-one 4.18 (dd, 24.36, 9.42 Hz, 1H),5.03 (m, 2H), 7.32 (m, 1H), 8.08 (d, 9.54 Hz, 1H) 34 4 1-{[6-chloro-2-395/397 2.60 (dd, 16.92, 8.08 Hz, 1H), 2.86 (dd,(trifluoromethyl)imidazo[1,2- 17.18, 8.97 Hz, 1H), 3.19 (m, 1H), 3.52(m, b]pyridazin-3-yl]methyl}-4- 1H), 3.63 (t, 8.71 Hz, 1H), 5.09 (m,2H), phenylpyrrolidin-2-one 7.14 (d, 7.58 Hz, 2H), 7.28 (m, 4H), 7.98(d, 9.35 Hz, 1H) 35 5-chloro-1-{[6-chloro-2- 401/403/405 3.60 (s, 2H),5.43 (s, 2H), 6.66 (d, 8.34 Hz, (trifluoromethyl)imidazo[1,2- 1H), 7.12(dd, 8.59, 1.89 Hz, 1H), 7.18 (d, b]pyridazin-3-yl]methyl}-1,3-dihydro-9.60 Hz, 1H), 7.22 (d, 0.51 Hz, 1H), 7.97 (d, 2H-indol-2-one 9.60 Hz,1H) 36 4 1-{[6-methoxy-2- 357 0.85 (m, 3H), 1.28 (m, 4H), 2.06 (dd,16.67, (trifluoromethyl)imidazo[1,2- 7.96 Hz, 1H), 2.26 (m, 1H), 2.53(dd, 16.67, b]pyridazin-3-yl]methyl}-4- 8.59 Hz, 1H), 2.76 (m, 1H), 3.27(m, 1H), propylpyrrolidin-2-one 4.03 (s, 3H), 4.97 (m, 2H), 6.85 (d,9.85 Hz, 1H), 7.84 (d, 9.85 Hz, 1H) 37 4 1-[(6-chloro-2- 333/335 0.89(m, 3H), 1.05 (m, 4H), 1.32 (m, 4H), cyclopropylimidazo[1,2-b]pyridazin-2.07 (dd, 16.42, 7.32 Hz, 1H), 2.29 (m, 2H),3-yl)methyl]-4-propylpyrrolidin-2-one 2.53 (dd, 16.42, 8.46 Hz, 1H),2.93 (m, 1H), 3.44 (m, 1H), 4.93 (s, 2H), 6.99 (d, 9.35 Hz, 1H), 7.75(d, 9.35 Hz, 1H) 38 4 1-{[6-isopropoxy-2- 385 0.83 (t, 7.18 Hz, 3H),1.27 (m, 4H), (trifluoromethyl)imidazo[1,2- 1.40 (dd, 6.04, 3.78 Hz,6H), 2.06 (dd, 16.37, b]pyridazin-3-yl]methyl}-4- 7.93 Hz, 1H), 2.25 (m,1H), 2.52 (dd, 16.62, propylpyrrolidin-2-one 8.81 Hz, 1H), 2.76 (dd,9.32, 6.92 Hz, 1H), 3.26 (m, 1H), 4.94 (m, 2H), 5.31 (m, 1H), 6.78 (d,9.82 Hz, 1H), 7.82 (d, 9.57 Hz, 1H) 39 4 1-{[6-(benzyloxy)-2- 433 0.86(m, 3H), 1.26 (m, 4H), 2.04 (dd, 16.42, (trifluoromethyl)imidazo[1,2-7.96 Hz, 1H), 2.23 (m, 1H), 2.50 (dd, 16.67, b]pyridazin-3-yl]methyl}-4-8.59 Hz, 1H), 2.73 (dd, 9.35, 6.95 Hz, 1H), propylpyrrolidin-2-one 3.23(m, 1H), 4.97 (m, 2H), 5.45 (s, 2H), 6.88 (d, 9.60 Hz, 1H), 7.37 (m,3H), 7.58 (d, 6.82 Hz, 2H), 7.87 (d, 9.85 Hz, 1H) 40 41-{[6-cyclopropyl-2- 367 0.85 (t, 8 Hz, 3H), 1.14-1.35 (m, 8H),(trifluoromethyl)imidazo[1,2- 2.08 (m, 2H), 2.25 (m, 1H), 2.55 (dd, 8 &16 Hz, b]pyridazin-3-yl]methyl}-4- 1H), 2.72 (dd, 8 & 12 Hz, 1H), 3.24(t, 8 Hz, propylpyrrolidin-2-one 1H), 4.98 (dd, 16 & 24 Hz, 2H), 7.06(d, 8 Hz, 1H), 7.85 (d, 8 Hz, 1H) 41 4 1-{[6-(dimethylamino)-2- 370 0.85(t, 7.20 Hz, 3H), 1.27 (m, 4H), (trifluoromethyl)imidazo[1,2- 2.06 (dd,16.67, 7.96 Hz, 1H), 2.24 (m, 1H), b]pyridazin-3-yl]methyl}-4- 2.52 (dd,16.67, 8.59 Hz, 1H), 2.73 (dd, 9.35, propylpyrrolidin-2-one 6.69 Hz,1H), 3.14 (s, 6H), 3.28 (m, 1H), 4.97 (d, 10.61 Hz, 2H), 6.89 (d, 10.1Hz, 1H), 7.71 (d, 10.10 Hz, 1H) 42 44-(2,2-difluorovinyl)-1-{[6-methoxy- 377 2.21 (dd, 16.83, 8.29 Hz, 1H),2.64 (dd, 2-(trifluoromethyl)imidazo[1,2- 16.83, 8.79 Hz, 1H), 2.90 (dd,9.54, 7.28 Hz, b]pyridazin-3-yl]methyl}pyrrolidin-2- 1H), 3.09 (m, 1H),3.38 (m, 1H), 4.03 (s, 3H), one 4.11 (dd, 9.54, 2.01 Hz, 1H), 4.18 (dd,9.54, 2.01 Hz, 1H), 4.99 (m, 2H), 6.84 (d, 9.54 Hz, 1H), 7.92 (d, 9.54Hz, 1H) 43 4 4-(2-chloro-2,2-difluoroethyl)-1-{[6- 417/419/421 2.22 (m,1H), 2.45 (m, 2H), 2.72 (m, 2H), chloro-2- 3.03 (m, 1H), 3.54 (m, 1H),5.02 (m, 2H), (trifluoromethyl)imidazo[1,2- 7.24 (d, 9.54 Hz, 1H), 8.00(d, 9.54 Hz, 1H) b]pyridazin-3-yl]methyl}pyrrolidin-2- one 44 41-{[6-(methylamino)-2- 356 0.85 (t, 7.15 Hz, 3H), 1.28 (m, 4H),(trifluoromethyl)imidazo[1,2- 2.07 (dd, 16.56, 7.91 Hz, 1H), 2.26 (m,1H), b]pyridazin-3-yl]methyl}-4- 2.53 (dd, 16.56, 8.53 Hz, 1H), 2.76(dd, 9.29, propylpyrrolidin-2-one 6.78 Hz, 1H), 3.00 (d, 5.02 Hz, 3H),3.27 (m, 1H), 4.68 (d, 4.77 Hz, 1H), 4.93 (m, 2H), 6.57 (d, 9.79 Hz,1H), 7.63 (d, 9.79 Hz, 1H) 45 4 1-{[6-hydroxy-2- 343 0.87 (t, 7.16 Hz,3H), 1.30 (m, 4H), 2.27 (m, (trifluoromethyl)imidazo[1,2- 2H), 2.66 (dd,16.58, 8.16 Hz, 1H), b]pyridazin-3-yl]methyl}-4- 2.79 (dd, 9.54, 6.66Hz, 1H), 3.31 (m, 2H), propylpyrrolidin-2-one 4.96 (m, 2H), 6.88 (d,9.54 Hz, 1H), 7.86 (d, 9.80 Hz, 1H) 46 4 1-{[6-(methylthio)-2- 373 0.87(m, 3H), 1.30 (m, 4H), 2.08 (m, 1H), (trifluoromethyl)imidazo[1,2- 2.28(m, 1H), 2.54 (dd, 16.58, 8.79 Hz, 1H), b]pyridazin-3-yl]methyl}-4- 2.67(s, 3H), 2.81 (dd, 9.54, 6.91 Hz, 1H), propylpyrrolidin-2-one 3.28 (m,1H), 5.04 (m, 2H), 7.03 (d, 9.54 Hz, 1H), 7.83 (d, 9.54 Hz, 1H) 47 44-(2-bromo-2,2-difluoroethyl)-1-{[6- 461/463/465 0.86 (t, 7.18 Hz, 3H),1.29 (m, 4H), 2.07 (m, chloro-2- 1H), 2.29 (m, 1H), 2.53 (dd, 16.62,8.56 Hz, (trifluoromethyl)imidazo[1,2- 1H), 2.80 (dd, 9.32, 7.05 Hz,1H), 3.31 (m, b]pyridazin-3-yl]methyl}pyrrolidin-2- 1H), 3.54 (s Hz,3H), 5.08 (m, 2H), 7.83 (d, one 9.57 Hz, 1H), 8.28 (d, 9.57 Hz, 1H) 48 41-{[6-(methylsulfonyl)-2- 405 0.86 (t, 7.16 Hz, 3H), 1.29 (m, 4H),(trifluoromethyl)imidazo[1,2- 2.08 (dd, 16.58, 8.16 Hz, 1H), 2.29 (m,1H), b]pyridazin-3-yl]methyl}-4- 2.53 (dd, 16.58, 8.67 Hz, 1H), 2.82(dd, 9.04, propylpyrrolidin-2-one 7.16 Hz, 1H), 3.29 (m, 1H), 3.54 (s,3H), 4.98 (m, 2H), 7.83 (d, 9.54 Hz, 1H), 8.26 (d, 9.54 Hz, 1H) 49 4 1CF₃COOH 1-{[6-(methylsulfinyl)-2- 389 0.84 (m, 3H), 1.24 (m, 4H), 2.04(m, 1H), (trifluoromethyl)imidazo[1,2- 2.27 (m, 1H), 2.50 (m, 1H), 2.81(m, 1H), b]pyridazin-3-yl]methyl}-4- 3.08 (s Hz, 3H), 3.31 (m, 1H), 5.04(m, 2H), propylpyrrolidin-2-one 7.89 (d, 9.57 Hz, 1H), 8.27 (d, 9.57 Hz,1H) 50 4 1-{[6-chloro-2- 401/403 2.23 (m, 3H), 2.66 (m, 2H), 3.02 (dd,9.29, (trifluoromethyl)imidazo[1,2- 7.03 Hz, 1H), 3.47 (m, 1H), 5.02 (m,2H), b]pyridazin-3-yl]methyl}-4-(2,2,2- 7.28 (m, 1H), 8.02 (d, 9.54 Hz,1H) trifluoroethyl)pyrrolidin-2-one 51 4 2 CF₃COOH1-[(6-chloro-2-cyclobutylimidazo[1,2- 347/349 0.89 (t, 7.05 Hz, 3H),1.32 (m, 4H), 2.11 (m, b]pyridazin-3-yl)methyl]-4- 3H), 2.45 (m, 6H),3.03 (dd, 9.57, 6.92 Hz, propylpyrrolidin-2-one 1H), 3.52 (m, 1H), 4.02(quint, 8.88 Hz, 1H), 4.82 (m, 2H), 7.40 (d, 9.57 Hz, 1H), 8.65 (d, 9.57Hz, 1H) 52 4 1-{[6-chloro-2-(4- 403/405 2.16 (dd, 16.83, 7.79 Hz, 1H),2.41 (s, 3H), methylphenyl)imidazo[1,2- 2.61 (dd, 16.83, 8.54 Hz, 1H),2.96 (m, 2H), b]pyridazin-3-yl]methyl}-4-(2,2- 3.38 (m, 1H), 4.00 (m,1H), 5.11 (s, 2H), difluorovinyl)pyrrolidin-2-one 7.11 (d, 9.29 Hz, 1H),7.32 (d, 8.04 Hz, 2H), 7.75 (d, 8.04 Hz, 2H), 7.93 (d, 9.29 Hz, 1H) 53 41-{[6-amino-2- 342 0.85 (t, 8 Hz, 3H), 1.21-1.35 (m, 4H),(trifluoromethyl)imidazo[1,2- 2.08 (dd, 8 & 16 Hz, 1H), 2.25 (m, 1H),2.55 (dd, b]pyridazin-3-yl]methyl}-4- 8 & 16 Hz, 1H), 2.75 (t, 8 Hz,1H), 3.25 (t, 8 Hz, propylpyrrolidin-2-one 1H), 4.78 (s, 2H), 4.89 (dd,16 & 36 Hz, 2H), 6.66 (d, 8 Hz, 1H), 7.74 (d, 8 Hz, 1H) 54 41-{[6-(ethylamino)-2- 370 0.85 (t, 7.03 Hz, 3H), 1.28 (m, 7H),(trifluoromethyl)imidazo[1,2- 2.06 (dd, 16.58, 7.91 Hz, 1H), 2.25 (m,1H), b]pyridazin-3-yl]methyl}-4- 2.52 (dd, 16.58, 8.54 Hz, 1H), 2.75(dd, 9.29, propylpyrrolidin-2-one 6.91 Hz, 1H), 3.26 (t, 8.67 Hz, 1H),3.50 (m, 2H), 4.54 (m, 1H), 4.92 (m, 2H), 6.54 (d, 9.54 Hz, 1H), 7.63(d, 9.80 Hz, 1H) 55 4 4-propyl-1-{[6-(propylamino)-2- 384 0.85 (t, 7.15Hz, 3H), 1.02 (t, 7.40 Hz, 3H), (trifluoromethyl)imidazo[1,2- 1.27 (m,4H), 1.67 (m, 2H), 2.06 (dd, 16.56,b]pyridazin-3-yl]methyl}pyrrolidin-2- 7.78 Hz, 1H), 2.25 (m, 1H), 2.52(dd, 16.56, one 8.66 Hz, 1H), 2.75 (dd, 9.54, 6.78 Hz, 1H), 3.25 (m,1H), 3.37 (m, 2H), 4.58 (t, 5.27 Hz, 1H), 4.91 (m, 2H), 6.55 (d, 9.54Hz, 1H), 7.63 (d, 9.79 Hz, 1H) 56 4 4-(2-bromo-2,2-difluoroethyl)-1-{[6-484/486 1.02 (m, 3H), 1.68 (m, 2H), 2.20 (m, 1H), (propylamino)-2- 2.49(m, 2H), 2.68 (m, 2H), 2.93 (m, 1H), (trifluoromethyl)imidazo[1,2- 3.39(m, 3H), 4.55 (s, 1H), 4.93 (q, 15.07 Hz,b]pyridazin-3-yl]methyl}pyrrolidin-2- 2H), 6.55 (m, 1H), 7.64 (m, 1H)one 57 4 4-(2,2-difluorovinyl)-1-{[6- 404 1.02 (t, 7.43 Hz, 3H), 1.68(m, 2H), (propylamino)-2- 2.20 (dd, 16.69, 8.07 Hz, 1H), 2.63 (dd,16.69, (trifluoromethyl)imidazo[1,2- 8.62 Hz, 1H), 2.88 (m, 1H), 3.07(m, 1H), b]pyridazin-3-yl]methyl}pyrrolidin-2- 3.37 (m, 3H), 4.14 (m,1H), 4.56 (t, 5.14 Hz, one 1H), 4.93 (m, 2H), 6.56 (d, 9.72 Hz, 1H),7.64 (d, 9.72 Hz, 1H) 58 4 4-(2,2-difluorovinyl)-1-{[6-methoxy- 399 2.17(dd, 16.58, 8.04 Hz, 1H), 2.40 (s, 3H), 2-(4-methylphenyl)imidazo[1,2-2.62 (dd, 16.58, 8.67 Hz, 1H), 2.86 (dd,b]pyridazin-3-yl]methyl}pyrrolidin-2- 9.54, 6.78 Hz, 1H), 2.98 (m, 1H),3.33 (m, 1H), one 4.02 (s, 3H), 5.07 (d, 3.01 Hz, 2H), 6.74 (d, 9.80 Hz,1H), 7.28 (d, 8.04 Hz, 2H), 7.68 (d, 8.29 Hz, 2H), 7.82 (d, 9.80 Hz, 1H)59 4 1 CF₃COOH 4-propyl-1-{[6-pyrrolidin-1-yl-2- 396 0.86 (t, 7.24 Hz,3H), 1.24 (m, 2H), 1.39 (m, (trifluoromethyl)imidazo[1,2- 2H), 2.05 (m,4H), 2.20 (m, 1H), 2.30 (m, 1H), b]pyridazin-3-yl]methyl}pyrrolidin-2-2.67 (dd, 16.85, 8.43 Hz, 1H), 2.82 (dd, one 9.71, 6.78 Hz, 1H), 3.32(m, 1H), 3.49 (t, 6.60 Hz, 4H), 4.96 (m, 2H), 6.83 (d, 9.89 Hz, 1H),7.94 (d, 9.89 Hz, 1H) 60 4 4-(2-bromo-2,2-difluoroethyl)-1-{[6- 457/4592.21 (m, 1H), 2.50 (m, 2H), 2.72 (m, 2H), methoxy-2- 2.95 (m, 1H), 3.43(m, 1H), 4.03 (s, 3H), (trifluoromethyl)imidazo[1,2- 4.99 (m, 2H), 6.87(d, 9.71 Hz, 1H), 7.86 (d, b]pyridazin-3-yl]methyl}pyrrolidin-2- 9.71Hz, 1H) one 61 4 1-{[6-(cyclopropylamino)-2- 402 0.58 (dd, 3.48, 1.65Hz, 2H), 0.89 (dd, 6.60, (trifluoromethyl)imidazo[1,2- 1.65 Hz, 2H),2.21 (dd, 16.67, 8.06 Hz, 1H), b]pyridazin-3-yl]methyl}-4-(2,2- 2.65 (m,2H), 2.90 (dd, 9.71, 6.96 Hz, 1H), difluorovinyl)pyrrolidin-2-one 3.08(m, 1H), 3.38 (m, 1H), 4.15 (m, 1H), 4.96 (m, 3H), 6.80 (d, 9.71 Hz,1H), 7.72 (d, 9.71 Hz, 1H) 62 4 1-[(6-chloro-2- 353/355 1.06 (m, 4H),2.23 (m, 2H), 2.64 (dd, 16.83, cyclopropylimidazo[1,2-b]pyridazin- 8.54Hz, 1H), 3.09 (m, 2H), 3.56 (t, 8.29 Hz, 3-yl)methyl]-4-(2,2- 1H), 4.19(dd, 24.36, 9.29 Hz, 1H), 4.94 (s, difluorovinyl)pyrrolidin-2-one 2H),7.01 (d, 9.29 Hz, 1H), 7.76 (d, 9.29 Hz, 1H) 63 44-(2,2-difluorovinyl)-1-{[6- 404 1.27 (m, 6H), 2.19 (m, 1H), 2.63 (dd,16.69, (isopropylamino)-2- 8.80 Hz, 1H), 2.89 (dd, 9.54, 7.24 Hz, 1H),(trifluoromethyl)imidazo[1,2- 3.07 (m, 1H), 3.36 (m, 1H), 4.13 (m, 2H),b]pyridazin-3-yl]methyl}pyrrolidin-2- 4.33 (m, 1H), 4.93 (m, 2H), 6.50(d, 9.72 Hz, one 1H), 7.64 (d, 9.72 Hz, 1H) 64 44-(2,2-difluorovinyl)-1-{[2- 347 2.23 (dd 8 & 20 Hz, 1H), 2.65 (dd 8 &20 Hz, (trifluoromethyl)imidazo[1,2- 1H), 2.93 (dd 8 & 12 Hz, 1H), 3.39(t 12 Hz, b]pyridazin-3-yl]methyl}pyrrolidin-2- 1H), 4.13 (dd 12 & 18Hz, 1H), 5.07 (dd 16 one & 40 Hz, 2H), 7.23 (dd, 1H), 8.07 (d, 1H), 8.52(d, 1H) 65 4 1-{[2-cyclopropyl-6- 376 0.99 (m, 7H), 1.67 (m, 2H), 2.17(m, 2H), (propylamino)imidazo[1,2- 2.63 (dd, 16.58, 8.54 Hz, 1H), 3.05(m, 2H), b]pyridazin-3-yl]methyl}-4-(2,2- 3.32 (q, 6.53 Hz, 2H), 3.52(t, 8.54 Hz, 1H), difluorovinyl)pyrrolidin-2-one 4.22 (m, 2H), 4.86 (s,2H), 6.35 (d, 9.54 Hz, 1H), 7.50 (d, 9.54 Hz, 1H) 66 41-({2-cyclopropyl-6-[(2- 380 0.99 (m, 4H), 2.08 (s, 1H), 2.20 (dd,16.81, fluoroethyl)amino]imidazo[1,2- 8.16 Hz, 1H), 2.63 (dd, 16.81,8.78 Hz, 1H), b]pyridazin-3-yl}methyl)-4-(2,2- 2.96 (dd, 9.54, 7.15 Hz,1H), 3.09 (d, 8.28 Hz, difluorovinyl)pyrrolidin-2-one 1H), 3.45 (m, 1H),3.72 (m, 2H), 4.16 (m, 1H), 4.66 (m, 3H), 4.85 (s, 2H), 6.41 (d, 9.54Hz, 1H), 7.54 (d, 9.54 Hz, 1H) 67 4 1-({2-cyclopropyl-6-[(2,2- 398 1.00(m, 4H), 2.09 (m, 1H), 2.20 (dd, 16.56, difluoroethyl)amino]imidazo[1,2-8.16 Hz, 1H), 2.63 (dd, 16.56, 8.78 Hz, 1H),b]pyridazin-3-yl}methyl)-4-(2,2- 2.98 (dd, 9.54, 7.28 Hz, 1H), 3.09 (m,1H), difluorovinyl)pyrrolidin-2-one 3.46 (m, 1H), 3.82 (m, 2H), 4.16 (m,1H), 4.62 (s, 1H), 4.86 (d, 1.76 Hz, 2H), 6.05 (m, 1H), 6.43 (d, 9.54Hz, 1H), 7.57 (d, 9.54 Hz, 1H) 68 4 1-({2-cyclopropyl-6-[(2,2,2- 4161.00 (m, 4H), 2.11 (m, 1H), 2.20 (dd, trifluoroethyl)amino]imidazo[1,2-16.83, 8.29 Hz, 1H), 2.63 (dd, 16.83, 8.79 Hz,b]pyridazin-3-yl}methyl)-4-(2,2- 1H), 2.97 (dd, 9.54, 7.16 Hz, 1H),difluorovinyl)pyrrolidin-2-one 3.08 (m, 1H), 3.45 (m, 1H), 4.15 (m, 3H),4.61 (t, 6.66 Hz, 1H), 4.87 (s, 2H), 6.44 (d, 9.54 Hz, 1H), 7.60 (d,9.54 Hz, 1H) 69 4 4-(2,2-difluoroethyl)-1-{[2- 349 1.95 (m, 3H), 2.17(m, 1H), 2.60 (m, 3H), (trifluoromethyl)imidazo[1,2- 2.94 (m, 1H), 3.40(m, 1H), 5.07 (m, 2H), b]pyridazin-3-yl]methyl}pyrrolidin-2- 5.80 (m,1H), 7.23 (dd, 9.29, 4.52 Hz, 1H), one 8.06 (d, 9.29 Hz, 1H), 8.51 (d,4.27 Hz, 1H) 70 4 1-{[2-cyclopropyl-6- 374 0.58 (d, 2.51 Hz, 1H), 0.83(d, 5.02 Hz, 2H), (cyclopropylamino)imidazo[1,2- 0.99 (m, 4H), 2.18 (m,2H), 2.63 (m, 2H), b]pyridazin-3-yl]methyl}-4-(2,2- 3.07 (m, 2H), 3.54(m, 1H), 4.18 (m, 1H), difluorovinyl)pyrrolidin-2-one 4.76 (s, 1H), 4.86(s, 2H), 6.61 (d, 9.54 Hz, 1H), 7.57 (d, 9.54 Hz, 1H) 71 41-[(6-chloro-2-cyclobutylimidazo[1,2- 367/369 1.99 (s, 1H), 2.15 (m,2H), 2.34 (dt, 8.29, b]pyridazin-3-yl)methyl]-4-(2,2- 2.61 Hz, 2H), 2.48(m, 2H), 2.62 (dd, 16.58, difluorovinyl)pyrrolidin-2-one 8.67 Hz, 1H),3.05 (m, 2H), 3.49 (m, 1H), 3.91 (t, 8.67 Hz, 1H), 4.16 (m, 1H), 4.82(s, 2H), 7.04 (d, 9.29 Hz, 1H), 7.88 (d, 9.29 Hz, 1H) 72 41-[(6-chloro-2- 419/421/423 1.09 (m, 4H), 2.29 (m, 1H), 2.50 (dd, 16.81,cyclopropylimidazo[1,2-b]pyridazin- 7.65 Hz, 1H), 2.85 (dd, 16.81, 9.03Hz, 1H), 3-yl)methyl]-4-(3-chloro-4- 3.29 (dd, 9.79, 6.53 Hz, 1H), 3.47(m, 1H), fluorophenyl)pyrrolidin-2-one 3.75 (m, 1H), 5.00 (q, 15.31 Hz,2H), 7.03 (m, 3H), 7.17 (dd, 6.78, 1.76 Hz, 1H), 7.75 (d, 9.29 Hz, 1H)73 4 1-{[6-(butylamino)-2- 418 0.97 (t, 7.33 Hz, 3H), 1.45 (m, 2H), 1.62(m, (trifluoromethyl)imidazo[1,2- 2H), 2.20 (dd, 16.67, 8.24 Hz, 1H),b]pyridazin-3-yl]methyl}-4-(2,2- 2.63 (dd, 16.67, 8.79 Hz, 1H), 2.89(dd, 9.34, difluorovinyl)pyrrolidin-2-one 7.24 Hz, 1H), 3.07 (m, 1H),3.38 (m, 3H), 4.14 (m, 1H), 4.50 (m, 1H), 4.93 (m, 2H), 6.55 (d, 9.71Hz, 1H), 7.64 (d, 9.71 Hz, 1H) 74 4 1-{[6-(cyclobutylamino)-2- 414 1.88(m, 4H), 2.22 (dd, 16.83, 8.16 Hz, 1H), (trifluoromethyl)imidazo[1,2-2.50 (m, 2H), 2.65 (dd, 16.83, 8.79 Hz, 1H),b]pyridazin-3-yl]methyl}-4-(2,2- 2.87 (dd, 9.54, 7.03 Hz, 1H), 3.07 (m,1H), difluorovinyl)pyrrolidin-2-one 3.35 (m, 1H), 4.14 (m, 1H), 4.32 (m,1H), 4.74 (d, 6.53 Hz, 1H), 4.93 (m, 2H), 6.53 (d, 9.80 Hz, 1H), 7.65(d, 9.54 Hz, 1H) 75 4 1-[(2-cyclopropyl-6- 349 1.01 (m, 4H), 2.18 (m,2H), 2.64 (dd, 16.83, methoxyimidazo[1,2-b]pyridazin-3- 8.67 Hz, 1H),3.06 (m, 2H), 3.50 (m, 1H), yl)methyl]-4-(2,2- 3.99 (s, 3H), 4.17 (dd,24.61, 9.42 Hz, 1H), difluorovinyl)pyrrolidin-2-one 4.91 (s, 2H), 6.64(d, 9.54 Hz, 1H), 7.67 (d, 9.29 Hz, 1H) 76 44-(2,2-difluorovinyl)-1-{[6-ethoxy-2- 391 1.45 (t, 7.03 Hz, 3H), 2.20(dd, 16.83, 8.29 Hz, (trifluoromethyl)imidazo[1,2- 1H), 2.63 (dd, 16.58,8.67 Hz, 1H), b]pyridazin-3-yl]methyl}pyrrolidin-2- 2.90 (dd, 9.54, 7.28Hz, 1H), 3.08 (m, 1H), one 3.37 (m, 1H), 4.14 (m, 1H), 4.43 (q, 7.03 Hz,2H), 4.97 (m, 2H), 6.84 (d, 9.80 Hz, 1H), 7.84 (d, 9.54 Hz, 1H) 77 44-(2,2-difluorovinyl)-1-{[6- 405 1.40 (dd, 6.05, 3.66 Hz, 6H), 2.20 (dd,isopropoxy-2- 16.67, 8.43 Hz, 1H), 2.63 (dd, 16.85, 8.79 Hz,(trifluoromethyl)imidazo[1,2- 1H), 2.91 (dd, 9.34, 7.33 Hz, 1H),b]pyridazin-3-yl]methyl}pyrrolidin-2- 3.08 (m, 1H), 3.36 (m, 1H), 4.14(m, 1H), one 4.89 (m, 1H), 5.03 (m, 1H), 5.31 (m, 1H), 6.79 (d, 9.71 Hz,1H), 7.82 (d, 9.89 Hz, 1H) 78 4 1-{[6-(cyclopropylmethoxy)-2- 417 0.43(m, 2H), 0.67 (m, 2H), 1.31 (m, 1H), (trifluoromethyl)imidazo[1,2- 2.20(dd, 16.67, 8.43 Hz, 1H), 2.63 (dd, b]pyridazin-3-yl]methyl}-4-(2,2-16.67, 8.79 Hz, 1H), 2.89 (dd, 9.53, 7.24 Hz,difluorovinyl)pyrrolidin-2-one 1H), 3.07 (m, 1H), 3.36 (m, 1H), 4.16 (m,3H), 4.96 (m, 2H), 6.88 (d, 9.71 Hz, 1H), 7.84 (d, 9.71 Hz, 1H) 79 41-{[6-(cyclobutylmethoxy)-2- 431 1.94 (m, 4H), 2.18 (m, 3H), 2.64 (dd,16.58, (trifluoromethyl)imidazo[1,2- 8.79 Hz, 1H), 2.80 (m, 1H), 2.90(dd, 9.54, b]pyridazin-3-yl]methyl}-4-(2,2- 7.03 Hz, 1H), 3.09 (m, 1H),3.37 (m, 1H), difluorovinyl)pyrrolidin-2-one 4.14 (m, 1H), 4.33 (d, 6.53Hz, 2H), 4.98 (m, 2H), 6.86 (d, 9.80 Hz, 1H), 7.83 (d, 9.80 Hz, 1H) 80 41-{[6-(cyclopropyloxy)-2- 403 0.86 (m, 4H), 2.21 (m, 1H), 2.63 (m, 1H),(trifluoromethyl)imidazo[1,2- 2.91 (m, 1H), 3.09 (m, 1H), 3.39 (m, 1H),b]pyridazin-3-yl]methyl}-4-(2,2- 4.15 (m, 1H), 4.37 (m, 1H), 5.01 (m,2H), difluorovinyl)pyrrolidin-2-one 6.80 (m, 1H), 7.85 (m, 1H) 81 44-(2,2-difluorovinyl)-1-{[6-propoxy-2- 405 1.06 (t, 7.40 Hz, 3H), 1.84(m, 2H), (trifluoromethyl)imidazo[1,2- 2.21 (dd, 16.81, 8.28 Hz, 1H),2.62 (m, 1H), b]pyridazin-3-yl]methyl}pyrrolidin-2- 2.90 (m, 1H), 3.08(m, 1H), 3.36 (m, 1H), one 4.15 (m, 1H), 4.34 (m, 2H), 4.97 (m, 2H),6.85 (d, 9.54 Hz, 1H), 7.84 (d, 9.54 Hz, 1H) 82 43-{[4-(2,2-difluorovinyl)-2- 372 2.23 (dd, 16.87, 8.25 Hz, 1H), 2.66(dd, oxopyrrolidin-1-yl]methyl}-2- 16.87, 8.25 Hz, 1H), 3.04 (m, 1H),3.15 (m, (trifluoromethyl)imidazo[1,2- 1H), 3.46 (t, 8.53 Hz, 1H), 4.19(m, 1H), b]pyridazine-6-carbonitrile 5.07 (m, 2H), 7.49 (d, 9.35 Hz,1H), 8.23 d, 9.35 Hz, 1H) 83 4 4-(2,2-difluorovinyl)-1-{[6-thien-3-yl-429 2.21 (m, 1H), 2.65 (m, 1H), 2.90 (dd, 9.35,2-(trifluoromethyl)imidazo[1,2- 7.15 Hz, 1H), 3.08 (m, 1H), 3.39 (m,1H), b]pyridazin-3-yl]methyl}pyrrolidin-2- 4.10 (m, 1H), 5.11 (m, 2H),7.49 (dd, 5.14, one 2.93 Hz, 1H), 7.62 (d, 9.54 Hz, 1H), 7.84 (dd, 5.14,1.19 Hz, 1H), 8.04 (m, 2H) 84 4 4-(2,2-difluorovinyl)-1-{[6-phenyl-2-423 2.14 (dd, 16.81, 8.28 Hz, 1H), 2.58 (dd,(trifluoromethyl)imidazo[1,2- 16.81, 8.78 Hz, 1H), 2.87 (dd, 9.54, 7.15Hz, b]pyridazin-3-yl]methyl}pyrrolidin-2- 1H), 3.01 (m, 1H), 3.35 (m,1H), 4.04 (m, 1H), one 5.08 (m, 2H), 7.48 (m, 3H), 7.66 (d, 9.54 Hz,1H), 8.01 (m, 3H) 85 4 4-(2,2-difluorovinyl)-1-{[6-methyl-2- 361 2.22(dd, 16.69, 8.07 Hz, 1H), 2.65 (m, 4H), (trifluoromethyl)imidazo[1,2-2.91 (dd, 9.54, 6.97 Hz, 1H), 3.08 (m, 1H),b]pyridazin-3-yl]methyl}pyrrolidin-2- 3.38 (m, 1H), 4.15 (m, 1H), 5.04(m, 2H), one 7.09 (d, 9.35 Hz, 1H), 7.91 (d, 9.35 Hz, 1H) 86 44-(2,2-difluorovinyl)-1-{[6-pyridin-3- 424 2.20 (dd, 16.81, 8.28 Hz,1H), 2.64 (dd, yl-2-(trifluoromethyl)imidazo[1,2- 16.81, 8.78 Hz, 1H),2.95 (m, 1H), 3.11 (m, b]pyridazin-3-yl]methyl}pyrrolidin-2- 1H), 3.43(m, 1H), 4.12 (m, 1H), 5.15 (m, 2H), one 7.54 (dd, 8.03, 4.77 Hz, 1H),7.76 (d, 9.79 Hz, 1H), 8.16 (d, 9.79 Hz, 1H), 8.54 (dt, 8.03, 2.26 Hz,1H), 8.78 (dd, 4.77, 1.85 Hz, 1H), 9.22 (d, 2.26 Hz, 1H) 87 44-propyl-1-{[2-(trifluoromethyl)- 331 0.91 (t, 7.15 Hz, 3H), 1.35 (m,4H), 2.00 (m, 5,6,7,8-tetrahydroimidazo[1,2- 3H), 2.33 (m, 1H), 2.47 (m,1H), 2.94 (t, b]pyridazin-3-yl]methyl}pyrrolidin-2- 6.65 Hz, 2H), 3.12(dd, 9.54, 7.03 Hz, 1H), one 3.34 (m, 2H), 3.56 (t, 8.78 Hz, 1H), 4.46(m, 2H), 6.49 (t, 6.15 Hz, 1H) 88 4 1-[(6-methylimidazo[2,1- 279 0.88(t, 7.05 Hz, 3H), 1.29 (m, 4H), b][1,3,4]thiadiazol-5-yl)methyl]-4- 2.07(dd, 16.62, 7.81 Hz, 1H), 2.27 (m, 1H), propylpyrrolidin-2-one 2.52 (dd,16.62, 8.56 Hz, 1H), 2.90 (dd, 9.57, 6.80 Hz, 1H), 3.40 (m, 1H), 4.73(m, 2H), 8.48 (s, 1H) 89 4 1-{[6-(4-methylphenyl)imidazo[2,1- 355 0.84(m, 3H), 1.25 (m, 4H), 2.06 (dd, 16.49,b][1,3,4]thiadiazol-5-yl]methyl}-4- 7.88 Hz, 1H), 2.21 (m, 1H), 2.39 (s,3H), propylpyrrolidin-2-one 2.53 (dd, 16.30, 8.52 Hz, 1H), 2.82 (m, 1H),3.30 (m, 1H), 5.00 (m, 2H), 7.27 (m, 2H), 7.63 (d, 7.88 Hz, 2H), 8.55(s, 1H) 90 4 1-[(2-cyclopropyl-6- 381 0.84 (m, 3H), 1.11-1.33 (m, 8H),2.04 (dd, phenylimidazo[2,1- 16.51, 7.70 Hz, 1H), 2.14-2.31 (m, 2H),b][1,3,4]thiadiazol-5-yl)methyl]-4- 2.51 (dd, 16.69, 8.53 Hz, 1H), 2.80(dd, propylpyrrolidin-2-one 9.35, 6.69 Hz, 1H), 3.29 (m, 1H), 4.94 (sHz, 2H), 7.32 (t, 7.43 Hz, 1H), 7.43 (m, 2H), 7.72 (m, 2H) 91 4 1CF₃COOH 1-[(6-methylimidazo[2,1- 278 0.90 (t, 7.17 Hz, 3H), 1.34 (m,4H), b][1,3]thiazol-5-yl)methyl]-4- 2.11 (dd, 16.85, 7.92 Hz, 1H), 2.37(m, 1H), propylpyrrolidin-2-one 2.57 (m, 4H), 2.98 (dd, 9.05, 7.04 Hz,1H), 3.43 (t, 8.68 Hz, 1H), 4.62 (m, 2H), 7.17 (d, 4.28 Hz, 1H), 8.04(d, 4.28 Hz, 1H) 92 4 1-[(6-chloroimidazo[2,1- 298/300 0.88 (t, 7.28 Hz,3H), 1.32 (m, 4H), b][1,3]thiazol-5-yl)methyl]-4- 2.06 (dd, 16.83, 7.79Hz, 1H), 2.31 (m, 1H), propylpyrrolidin-2-one 2.51 (dd, 16.83, 8.67 Hz,1H), 2.99 (dd, 9.80, 6.91 Hz, 1H), 3.47 (m, 1H), 4.61 (m, 2H), 6.84 (d,4.52 Hz, 1H), 7.77 (d, 4.52 Hz, 1H) 93 4 1-[(2,6-dichloroimidazo[2,1-332/334/336 0.90 (t, 7.28 Hz, 3H), 1.22-1.44 (m, 4H),b][1,3]thiazol-5-yl)methyl]-4- 2.07 (dd, 16.81, 8.03 Hz, 1H), 2.27-2.40(m, propylpyrrolidin-2-one 1H), 2.53 (dd, 16.81, 8.78 Hz, 1H), 2.99 (dd,9.79, 6.90 Hz, 1H), 3.47 (m, 1H), 4.55 (m, 2H), 7.81 (s Hz, 1H) 95 41-(3H-imidazo[4,5-b]pyridin-7- 259 0.88 (t, J 6.90 Hz, 3H), 1.22-1.45(m, 4H), ylmethyl)-4-propylpyrrolidin-2-one 2.09-2.22 (m, 1H), 2.31-2.42(m, 1H), 2.59 (dd, J 16.06, 8.53 Hz, 1H), 3.03 (t, J 8.79 Hz, 1H), 3.50(t, J 8.53 Hz, 1H), 4.61 (s, 1H), 4.97 (m, 1H), 7.08-7.15 (m, 1H),8.28-8.53 (m, 2H), 11.26 and 13.27 (two s broad, 1H) 96 41-(3H-imidazo[4,5-b]pyridin-7- 293 (DMSO): 2.49-2.58 (m, 1H), 2.78 (dd,J ylmethyl)-4-phenylpyrrolidin-2-one 16.31, 8.78 Hz, 1H), 3.31-3.38 (m,1H overlapped with solvent signal), 3.65 (m, 1H), 3.76 (t, J 8.54 Hz,1H), 4.84 (s (broad), 2H), 7.08 (d, J 4.77 Hz, 1H), 7.20-7.26 (m, 1H),7.28-7.33 (m, 4H), 8.30 (s (broad), 1H), 8.43 (s (broad), 1H), 13.12 (s(broad), 1H) 97 4 4-phenyl-1-[(5-phenyl-3H- 369 (DMSO): 2.49-2.59 (m,1H), 2.82 (dd, J imidazo[4,5-b]pyridin-7- 16.56, 8.78 Hz, 1H), 3.38 (dd,J 9.29, 7.03 Hz, yl)methyl]pyrrolidin-2-one 1H, overlapped with solventsignal), 3.66 (m, 1H), 3.82 (t, J 8.78 Hz, 1H), 4.88 (s, 2H), 7.20-7.25(m, 1H), 7.27-7.32 (m, 5H), 7.42 (t, J 7.28 Hz, 1H), 7.50 (t, J 7.28 Hz,2H), 7.58 (s, 1H), 8.03 (d, J 7.53 Hz, 2H), 8.46 (s, 1H) 98 44-phenyl-1-{[5-(trifluoromethyl)-3H- 361 (DMSO): 2.55 (m, 1H), 2.81 (dd,16.58, 8.79 Hz, imidazo[4,5-b]pyridin-7- 1H), 3.38 (m, 2H), 3.64 (m,1H), yl]methyl}pyrrolidin-2-one 3.79 (m, 1H), 4.89 (s, 2H), 7.27 (m,5H), 7.52 (s Hz, 1H), 8.73 (s Hz, 1H), 13.23-13.75 (broad singlet, 1H)99 4 1-[(6-bromo-3H-imidazo[4,5- 337/339 0.81 (t, J 7.15 Hz, 3H), 1.22(m, 4H), b]pyridin-7-yl)methyl]-4- 1.98 (dd, J 16.31, 7.65 Hz, 1H), 2.24(m, 1H), propylpyrrolidin-2-one 2.41 (dd, J 16.31, 8.53 Hz, 1H), 2.79(dd, J 9.03, 6.78 Hz, 1H), 3.25 (t, J 8.66 Hz, 1H), 4.79 (m, 2H), 8.48(d, J 7.53 Hz, 2H), 13.28 (s, 1H) 100 4 1-[(2-phenyl-3H-imidazo[4,5- 3350.84 (t, J 7.15 Hz, 3H), 1.20-1.34 (m, 2H), b]pyridin-7-yl)methyl]-4-1.34-1.40 (m, 2H), 2.08 (dd, J 16.31, 7.78 Hz, propylpyrrolidin-2-one1H), 2.36 (m, 1H), 2.47 (m, 1H, overlapped with solvent signal), 3.05(dd, J 9.29, 7.03 Hz, 1H), 3.51 (t, J 8.66 Hz, 1H), 4.80 (s, 2H), 7.01(d, J 4.77 Hz, 1H), 7.50-7.60 (m, 3H), 8.23-8.31 (m, 3H), 13.57 (s, 1H)101 4 1-[(5-methyl-3H-imidazo[4,5- 273 0.85 (t, J 7.15 Hz, 3H),1.19-1.32 (m, 2H), b]pyridin-7-yl)methyl]-4- 1.34-1.45 (m, 2H), 2.04(dd, J 16.31, 7.65 Hz, propylpyrrolidin-2-one 1H), 2.32 (m, 1H), 2.45(m, 1H, overlapped with solvent signal), 2.53 (s, 3H), 2.97 (t, J 7.0Hz, 1H), 3.44 (t, J 8.66 Hz, 1H), 4.69 (s, 2H), 6.86 (s, 1H), 8.30 (s,1H), 12.88 (s, 1H) 102 4 1-[(2-methyl-3H-imidazo[4,5- 273 (DMSO): 0.85(t, J 7.15 Hz, 3H), b]pyridin-7-yl)methyl]-4- 1.20-1.30 (m, 2H),1.32-1.39 (m, 2H), 2.05 (dd, J propylpyrrolidin-2-one 16.31, 7.65 Hz,1H), 2.32 (m, 1H), 2.45 (m, 1H overlapped with solvent signal), 2.52 (s,3H), 2.96 (t, J 9.03 Hz, 1H), 3.42 (t, J 8.66 Hz, 1H), 4.69 (s (broad),2H), 6.90 (d, J 5.02 Hz, 1H), 8.16 (s, 1H), 12.80 (s, 1H, another broadsignal appears at 12.4 ppm) 103 4 4-propyl-1-{[5-(trifluoromethyl)-3H-327 0.84 (t, J 7.15 Hz, 3H), 1.18-1.30 (m, 2H), imidazo[4,5-b]pyridin-7-1.31-1.40 (m, 2H), 2.05 (dd, J 16.31, 7.28 Hz,yl]methyl}pyrrolidin-2-one 1H), 2.32 (m, 1H), 2.48 (m, 1H overlappedwith solvent signal), 3.00 (dd, J 9.29, 6.40 Hz, 1H), 3.48 (t, J 8.66Hz, 1H), 4.81 (s, 2H), 7.45 (s, 1H), 8.72 (s, 1H) 104 41-[(6-methyl-3H-imidazo[4,5- 273 0.79 (t, J 7.15 Hz, 3H), 1.11-1.28 (m,4H), b]pyridin-7-yl)methyl]-4- 1.98 (dd, J 16.31, 7.78 Hz, 1H), 2.21 (m,1H), propylpyrrolidin-2-one 2.32 (s, 3H), 2.42 (dd, J 16.56, 8.66 Hz,1H), 2.76 (dd, J 9.54, 6.78 Hz, 1H), 3.21 (t, J 9.3 Hz, 1H), 4.71 (d, J14.3 Hz, 1H), 4.78 (d, J 14.3 Hz, 1H), 8.19 (s, 1H), 8.37 (s, 1H), 12.82(s (broad), 1H) 105 4 1-[(6-phenyl-3H-imidazo[4,5- 335 0.78 (t, J 6.90Hz, 3H), 1.06-1.18 (m, 4H), b]pyridin-7-yl)methyl]-4- 1.67 (dd, J 15.81,7.78 Hz, 1H), 1.98 (m, 1H), propylpyrrolidin-2-one 2.12 (dd, J 15.81,8.5 Hz, 1H), 2.56 (s, 1H), 3.01 (s, 1H), 4.76 (s, 2H), 7.38-7.48 (m,5H), 8.20 (s, 1H), 8.48 (s, 1H), 13.11 (s (broad), 1H) 106 A-1§1-[1-(1H-imidazol-4- 194 1.00 (t, J 7.0, 3H), 1.90-2.10 (m, 4H),yl)propyl]pyrrolidin-2-one 2.30-2.40 (m, 2H), 3.28 (m, 1H), 3.39 (m,1H), 4.90 (m, 1H), 6.90 (s, 1H), 7.60 (s, 1H) 107 B-1§1-[1-(1H-imidazol-4- 194 1.00 (t, J 7.0, 3H), 1.90-2.10 (m, 4H),yl)propyl]pyrrolidin-2-one 2.30-2.40 (m, 2H), 3.28 (m, 1H), 3.39 (m,1H), 4.90 (m, 1H), 6.90 (s, 1H), 7.60 (s, 1H) 1081-[(5-methyl-1H-imidazol-4- 180 (DMSO): 1.85 (m, 2H), 2.10 (s, 3H), 2.15(t, J yl)methyl]pyrrolidin-2-one 7.1 Hz, 2H), 3.20 (t, J 7.1 Hz, 2H),4.20 (s, 2H), 7.35 (s, 1H) 109 1-[(2-methyl-1H-imidazol-4- (DMSO): 1.90(m, 2H), 2.25 (t, J 7 Hz and s, yl)methyl]pyrrolidin-2-one 5H), 3.25 (t,J 7 Hz, 2H), 4.20 (s, 2H), 6.75 (s, 1H) 110 4 1 CF₃COOH1-(1H-imidazol-4-ylmethyl)-4- (CD₃CN): 0.91 (t, J 7.17 Hz, 3H);propylpyrrolidin-2-one 1.29-1.43 (m, 4H), 1.95-2.06 (m, 1H overlappedwith solvent); 2.33-2.48 (m, 2H); 3.01 (t, J 7.55 Hz, 1H), 3.47 (t, J8.19 Hz, 1H); 4.48 (s, 2H), 7.29 (s, 1H), 8.43 (s, 1H) 111 4,4 1 CF₃COOH1-({1-[(2-oxo-4-propylpyrrolidin-1- 0.80-0.95 (m, 6H), 1.25-1.50 (m,8H), yl)methyl]-1H-imidazol-4-yl}methyl)- 2.14 (m, 2H), 2.30-2.65 (m,4H), 3.06 (dd, J 8.0, 4-propylpyrrolidin-2-one 16.0 Hz, 2H), 3.56 (t, J8.0 Hz, 2H), 4.45 (d, J 8.0 Hz, 1H), 4.55 (d, J 8.0 Hz, 1H), 5.50 (s,2H), 7.19 (s, 1H), 8.62 (s, 1H) 112 4 1-[(5-chloro-1H-imidazol-4-330/332 2.54 (dd, J 17.0, 7.2 Hz, 1H), 2.85 (dd, J yl)methyl]-4-(2,3,5-17.2, 8.7 Hz, 1H), 3.39-3.51 (m, 1H), trifluorophenyl)pyrrolidin-2-one3.77-3.92 (m, 2H), 4.43 (d, J 17.0 Hz, 1H), 4.50 (d, J 17.0 Hz, 1H),6.58-6.72 (m, 1H), 6.79-6.92 (m, 1H), 7.45-7.56 (m, 1H), 10.67-11.13 (s(broad), 1H) 113 4 1-[(5-bromo-1H-imidazol-4- 374/376 2.54 (dd, J 8.0,17.0 Hz, 1H), 2.85 (dd, J yl)methyl]-4-(2,3,5- 6.0, 16.0 Hz, 1H),3.41-3.51 (m, 1H), trifluorophenyl)pyrrolidin-2-one 3.79-3.90 (m, 2H),4.41 (d, J 15.0 Hz, 1H), 4.53 (d, J 15.0 Hz, 1H), 6.58-6.75 (m, 1H),6.78-6.99 (m, 1H), 7.43-7.73 (m, 1H), 11.03-11.38 (m, 1H) 1141-[(5-bromo-1H-imidazol-4- 326/328/330 3.63 (s, 2H), 4.80 (s, 2H), 6.74(d, J 8.28 Hz, yl)methyl]-5-chloro-1,3-dihydro-2H- 1H), 7.28 (d, 8.28Hz, 1H), 7.35 (s, 1H), indol-2-one 7.59 (s, 1H), 12.48 (s, 1H) 1151-(1H-imidazol-5-ylmethyl)pyrrolidin- 2.00 (m, 2H), 2.89 (t, J 8.2, 2H),3.44 (t, J 2-one 7.0, 2H), 4.42 (s, 2H), 6.94 (s, 1H), 7.58 (s, 1H) 1161 HCl 1-[(1-methyl-1H-imidazol-5- 180 (DMSO) 1.90 (m, 2H), 2.25 (t, J 8Hz, 2H), yl)methyl]pyrrolidin-2-one 3.25 (t, J 7.0, 2H), 3.85 (s, 3H),4.42 (s, 2H), 7.6 (s, 1H), 9.1 (s, 1H) 1171-methyl-5-[(2-oxopyrrolidin-1- 205 1.99-2.15 (m, 2H), 2.36-3.48 (m,2H), yl)methyl]-1H-imidazole-4- 3.37-3.46 (m, 2H), 3.72 (s, 3H), 4.58(s, 2H), carbonitrile 7.46 (s, 1H) 118 4 1 HCl1-(1H-imidazol-5-ylmethyl)-4- 242 2.62 (dd, J 9.0, 17.1 Hz, 1H), 2.84(dd, J phenylpyrrolidin-2-one 8.8, 17.1 Hz, 1H), 3.43 (t, J 7.6 Hz, 1H),3.60-3.70 (m, 1H), 3.83 (t, J 8.7 Hz, 1H), 4.59 (d, J 15.0 Hz, 1H), 4.75(d, J 15.0 Hz, 1H), 7.13-7.21 (m, 5H), 7.37 (s, 1H), 9.23 (s, 1H), 10.76(s (broad), 1H) 119 4 1 HCl 1-[(1-methyl-1H-imidazol-5- 256 2.61 (dd, J8.0, 17.0 Hz, 1H), 2.85 (dd, J yl)methyl]-4-phenylpyrrolidin-2-one 8.0,17.0 Hz, 1H), 3.32 (dd, J 8.85, 7.06 Hz, 1H), 3.52-3.80 (m, 2H), 4.00(s, 3H), 4.50 (d, J 15.8 Hz, 1H), 4.74 (d, J 15.8 Hz, 1H), 7.13-7.38 (m,5H), 7.46 (s, 1H), 9.56 (s, 1H) 120 1-[(4-methoxy-1-methyl-1H- 2101.87-2.05 (m, 2H), 2.37 (t, J 7.0 Hz, 2H),imidazol-5-yl)methyl]pyrrolidin-2-one 3.30 (t, J 7.0 Hz, 2H), 3.57 (s,3H), 3.91 (s, 3H), 4.38 (s, 2H), 7.05 (s, 1H) 121 4 1 HCl1-[(1-methyl-1H-imidazol-5- 222 0.90 (t, J 7.06 Hz, 3H), 1.21-1.47 (m,4H), yl)methyl]-4-propylpyrrolidin-2-one 2.09 (dd, J 16.56, 7.86 Hz,1H), 2.26-2.48 (m, 2H), 2.55 (dd, J 16.56, 8.54 Hz, 1H), 2.91 (dd, J9.38, 6.94 Hz, 1H), 3.40 (dd, J 9.3, 8.0 Hz, 1H), 3.96 (s, 3H), 4.44 (d,J 15.8 Hz, 1H), 4.61 (d, J 15.8 Hz, 1H), 7.41 (s, 1H), 9.54 (s, 1H) 1224 1-methyl-5-[(2-oxo-4- 0.91 (t, J 7 Hz, 3H), 1.35 (m, 4H), 2.08 (dd,propylpyrrolidin-1-yl)methyl]-1H- J 16.5, 7.8 Hz, 1H), 2.35 (m, 1H),2.54 (m, imidazole-4-carbonitrile 1H), 3.00 (m, 1H), 3.48 (m, 1H), 3.70(s, 3H), 4.56 (q, J 15.6 Hz, 2H), 7.46 (s, 1H) 123 41-methyl-5-[(2-oxo-4- 265 0.88 (t, J 6.9 Hz, 3H), 1.30 (m, 3H),propylpyrrolidin-1-yl)methyl]-1H- 2.05 (m, 1H), 2.26 (m, 1H), 2.50 (m,1H), imidazole-4-carboxamide 2.97 (dd, J 10.4, 6.9 Hz, 1H), 3.49 (dd, J10.2, 7.9 Hz, 1H), 3.69 (s, 3H), 4.93 (s, 2H), 5.35 (s broad, 1H), 7.04(s broad, 1H), 7.36 (s, 1H) 124 4 1 HCl N-benzyl-2-{5-[(2-oxo-4- 355(DMSO): 0.84 (t, J 6.94 Hz, 3H), propylpyrrolidin-1-yl)methyl]-1H-1.08-1.39 (m, 4H), 1.77-1.97 (m, 1H), 2.07-2.36 (m, 2H),imidazol-1-yl}acetamide 2.79 (m, 1H), 3.20-3.6 (m, 1H, overlapped withsolvent signal), 4.32 (m, 2H), 4.47 (m, 2H), 4.97 (d, J 1.53 Hz, 2H),7.23-7.38 (m, 5H), 7.62 (d, J 0.61 Hz, 1H), 8.90 (m, 1H), 8.98 (m, 1H)125 4 1 CF₃COOH 1-methyl-5-[(2-oxo-4- 247 0.91 (t, J 7.0 Hz, 3H), 1.34(m, 4H), propylpyrrolidin-1-yl)methyl]-1H- 2.13 (m, 1H), 2.32 (d, J 7.9Hz, 1H), 2.57 (m, 1H), imidazole-2-carbonitrile 2.89 (dd, J 9.5, 6.9 Hz,1H), 3.36 (m, 1H), 3.80 (s, 3H), 4.47 (m, 2H), 7.13 (s, 1H) 126 41-[(4-chloro-1H-imidazol-5- 242/244 0.91 (t, J 7.30 Hz, 3H), 1.24-1.35(m, 2H), yl)methyl]-4-propylpyrrolidin-2-one 1.36-1.44 (m, 2H), 2.06(dd, J 16.62, 7.81 Hz, 1H), 2.37 (m, 1H), 2.51 (dd, J 16.62, 8.81 Hz,1H), 3.08 (dd, J 9.82, 6.92 Hz, 1H), 3.54 (dd, J 9.57, 8.18 Hz, 1H),4.35 (m, 2H), 7.44 (s, 1H), 10.78 (s, 1H) 127 41-methyl-5-{[2-oxo-4-(2,3,5- 335 (DMSO): 2.59 (dd, J 16.93, 5.43 Hz,1H), trifluorophenyl)pyrrolidin-1- 2.89 (dd, J 17.18, 7.07 Hz, 1H), 3.42(m, 1H), yl]methyl}-1H-imidazole-4- 3.76 (d, J 2.27 Hz, 3H), 3.83 (s,2H), carbonitrile 4.66 (s, 2H), 6.65 (dd, J 5.31, 2.78 Hz, 1H),6.80-6.90 (m, 1H), 7.50 (s, 1H) 128 4 1-[(4-bromo-1-methyl-1H-imidazol-300/302 (DMSO): 0.90 (t, J 7.20 Hz, 3H),5-yl)methyl]-4-propylpyrrolidin-2-one 1.24-1.44 (m, 4H), 2.06 (dd, J16.67, 7.83 Hz, 1H), 2.31 (m, 1H), 2.52 (dd, J 16.93, 8.72 Hz, 1H), 2.93(dd, J 9.85, 6.82 Hz, 1H), 3.42 (dd, J 9.60, 8.08 Hz, 1H), 3.65 (s, 3H),4.44 (m, 2H), 7.37 (s, 1H) 129 4 1-[(2,4-dichloro-1-methyl-1H-290/292/294 0.91 (t, J 7.07 Hz, 3H), 1.26-1.36 (m, 2H),imidazol-5-yl)methyl]-4- 1.36-1.45 (m, 2H), 2.07 (dd, J 16.67, 7.96 Hz,propylpyrrolidin-2-one 1H), 2.32 (m, 1H), 2.52 (dd, J 16.67, 8.59 Hz,1H), 2.93 (dd, J 9.60, 6.95 Hz, 1H), 3.45 (t, J 9.35 Hz, 1H), 3.58 (s,3H), 4.46 (m, 2H), 4.36 (d, J 15.6 Hz, 1H), 4.47 (d, J 15.6 Hz, 1H) 1304 1 CF₃COOH benzyl 1-methyl-5-[(2-oxo-4- 371 0.92 (t, J 7.18 Hz, 3H),1.24-1.37 (m, 2H), propylpyrrolidin-1-yl)methyl]-1H- 1.37-1.49 (m, 2H),2.14 (dd, J 16.87, 7.81 Hz, imidazol-2-ylcarbamate 1H), 2.37 (m, 1H),2.60 (dd, J 16.87, 8.56 Hz, 1H), 2.91 (t, J 7.68 Hz, 1H), 3.38 (t, J8.31 Hz, 1H), 3.60 (s, 3H), 4.38 (d, J 15.7 Hz, 1H), 4.55 (d, J 15.7 Hz,1H), 5.24 (s, 2H), 7.02 (s, 1H), 7.36 (m, 5H), 8.62 (s (broad), 2H) 1314 1-[(4-chloro-1-methyl-1H-imidazol-5- 256/258 0.90 (t, J 7.20 Hz, 3H),1.24-1.41 (m, 4H), yl)methyl]-4-propylpyrrolidin-2-one 2.06 (dd, J16.67, 7.96 Hz, 1H), 2.31 (m, 1H), 2.52 (dd, J 16.93, 8.72 Hz, 1H), 2.93(dd, J 9.85, 6.82 Hz, 1H), 3.42 (dd, J 9.85, 8.08 Hz, 1H), 3.63 (s, 3H),4.40 (d, J 15.4 Hz, 1H), 4.49 (d, J 15.4 Hz, 1H), 7.31 (s, 1H) 132 4 1CF₃COOH 1-[(2-bromo-1-methyl-1H-imidazol- 300/302 0.91 (t, J 7.30 Hz,3H), 1.30-1.45 (m, 4H), 5-yl)methyl]-4-propylpyrrolidin-2-one 2.13 (dd,J 17.12, 8.18 Hz, 1H), 2.35 (m, 1H), 2.59 (dd, J 16.87, 8.81 Hz, 1H),2.91 (dd, J 9.57, 7.05 Hz, 1H), 3.39 (dd, J 9.57, 8.06 Hz, 1H), 3.65 (s,3H), 4.37 (d, J 15.7 Hz, 1H), 4.54 (d, J 15.4 Hz, 1H), 7.21 (s, 1H) 1334 1 CF₃COOH 1-[(2-chloro-1-methyl-1H-imidazol-5- 256/258 0.92 (t, J 7.18Hz, 3H), 1.30 (m, 2H), yl)methyl]-4-propylpyrrolidin-2-one 1.42 (m, 2H),2.18 (dd, J 17.12, 8.18 Hz, 1H), 2.38 (m, 1H), 2.64 (dd, J 16.87, 8.69Hz, 1H), 2.96 (dd, J 9.57, 7.05 Hz, 1H), 3.43 (m, 1H), 3.66 (s, 3H),4.48 (m, 2H), 7.15 (s, 1H) 134 5-chloro-1-(1H-imidazol-5-ylmethyl)-248/250 3.60 (s, 2H), 4.73 (s, 2H), 7.04 (s, 1H),1,3-dihydro-2H-indol-2-one 7.05 (d, J 8.3 Hz, 1H), 7.25 (d, J 8.3 Hz,1H), 7.53 (s, 1H), 11.94 (s, 1H) 135 4 1-[(2,4-dichloro-1H-imidazol-5-364/366/368 2.60 (dd, J 7.5, 17.1 Hz, 1H), 2.91 (dd, Jyl)methyl]-4-(2,3,5- 17.07, 8.78 Hz, 1H), 3.47 (dd, J 10.0, 13.0 Hz,trifluorophenyl)pyrrolidin-2-one 1H), 3.83-3.92 (m, 2H), 4.41 (d, J 15.3Hz, 1H) 4.48 (d, J 15.3 Hz, 1H), 6.67-6.71 (m, 1H), 6.83-6.90 (m, 1H),11.63 (s (broad), 1H) 136 4 1-[(2,4-dichloro-1-methyl-1H- 378/380/3822.57 (m, 1H), 2.86 (m, 1H), 3.35 (m, 1H),imidazol-5-yl)methyl]-4-(2,3,5- 3.63 (s, 3H), 3.74-3.83 (m, 2H), 4.48(d, J trifluorophenyl)pyrrolidin-2-one 15.8 Hz, 1H) 4.54 (d, J 15.8 Hz,1H), 6.67-6.71 (m, 1H), 6.83-6.90 (m, 1H) 137 41-[(2-chloro-1-methyl-1H-imidazol-5- 344/346 2.58 (dd, J 17.12, 7.81 Hz,1H), 2.88 (dd, J yl)methyl]-4-(2,3,5- 17.0, 9.19 Hz, 1H), 3.28 (dd, J9.82, 6.55 Hz, trifluorophenyl)pyrrolidin-2-one 1H), 3.58 (s, 3H), 3.68(t, J 9.54 Hz, 1H), 3.74-3.82 (m, 1H), 4.47 (d, J 15.8 Hz, 1H), 4.51 (d,J 15.8 Hz, 1H), 6.60-6.64 (m, 1H), 6.82-6.90 (m, 1H), 6.91 (s, 1H) 138 41 CF₃COOH 1-[(4-bromo-1-methyl-1H-imidazol- 388/390 2.59 (dd, J 17.07,7.53 Hz, 1H), 2.88 (dd, J 5-yl)methyl]-4-(2,3,5- 17.07, 8.78 Hz, 1H),3.37 (dd, J 10.8, 3.01 Hz, trifluorophenyl)pyrrolidin-2-one 1H),3.74-3.84 (m, 5H with a s, 3H at 3.76), 4.55 (s, 2H), 6.63 (s (broad),1H), 6.60-6.68 (m, 1H), 6.82-6.90 (m, 1H), 7.74 (s, 1H) 1395-chloro-1-[(1-methyl-1H-imidazol-5- 262/264 3.56 (s, 2H), 3.64 (s, 3H),4.89 (s, 2H), yl)methyl]-1,3-dihydro-2H-indol-2- 6.88 (d, J 8.53 Hz,1H), 7.13 (s, 1H), one 7.20 (d, J 8.28 Hz, 1H), 7.23 (s, 1H), 7.40 (s,1H) 140 4 1 CF₃COOH 1-[(4-chloro-1-methyl-1H-imidazol-5- 344 2.57 (dd, J17.3, 6.7 Hz, 1H), 2.87 (dd, J yl)methyl]-4-(2,3,5- 17.3, 6.7 Hz, 1H),3.36 (m, 1H), 3.72 (s, 3H), trifluorophenyl)pyrrolidin-2-one 3.74-3.82(m, 2H), 4.54 (s, 2H), 6.59-6.66 (m, 1H), 6.82-6.89 (m, 1H), 7.53 (s,1H) 141 4 1-(1H-indol-2-ylmethyl)-4- 257 0.83 (t, 7.05 Hz, 3H), 1.27 (m,4H), 2.08 (m, propylpyrrolidin-2-one 1H), 2.23 (m, 1H), 2.54 (dd, 16.37,8.56 Hz, 1H), 2.86 (dd, 9.57, 6.80 Hz, 1H), 3.34 (m, 1H), 4.63 (m, 2H),7.13 (m, 2H), 7.21 (m, 1H), 7.38 (d, 8.06 Hz, 1H), 7.68 (d, 8.06 Hz,1H), 8.32 (s, 1H) 142 4 1-(1H-indol-3-ylmethyl)-4- 257 0.83 (t, 7.04 Hz,3H), 1.25 (m, 4H), propylpyrrolidin-2-one 2.09 (dd, 16.35, 7.80 Hz, 1H),2.22 (m, 1H), 2.54 (dd, 16.35, 8.55 Hz, 1H), 2.86 (dd, 9.31, 7.04 Hz,1H), 3.34 (t, 8.80 Hz, 1H), 4.62 (m, 2H), 7.16 (m, 3H), 7.37 (d, 8.05Hz, 1H), 7.68 (d, 7.80 Hz, 1H), 8.54 (s, 1H) 143 43-[(2-oxo-4-propylpyrrolidin-1- 282 0.85 (t, 7.18 Hz, 3H), 1.29 (m, 4H),yl)methyl]-1H-indole-5-carbonitrile 2.11 (dd, 16.62, 7.81 Hz, 1H), 2.28(m, 1H), 2.57 (dd, 16.62, 8.69 Hz, 1H), 2.89 (dd, 9.57, 6.80 Hz, 1H),3.37 (m, 1H), 4.62 (m, 2H), 7.32 (d, 2.27 Hz, 1H), 7.44 (m, 2H), 8.04(s, 1H), 9.35 (s, 1H) 144 4 1-[(2-methyl-1H-indol-3-yl)methyl]-4- 2710.83 (t, 7.04 Hz, 3H), 1.26 (m, 4H), propylpyrrolidin-2-one 2.07 (dd,16.60, 7.92 Hz, 1H), 2.20 (m, 1H), 2.45 (s, 3H), 2.52 (dd, 16.35, 8.55Hz, 1H), 2.83 (dd, 9.81, 6.92 Hz, 1H), 3.30 (m, 1H), 4.58 (m, 2H), 7.11(m, 2H), 7.30 (m, 1H), 7.57 (d, 7.55 Hz, 1H), 8.07 (s, 1H) 145 41-[(7-methoxy-1H-indol-3-yl)methyl]- 287 0.83 (t, 7.17 Hz, 3H), 1.27 (m,4H), 4-propylpyrrolidin-2-one 2.08 (dd, 16.35, 8.05 Hz, 1H), 2.21 (m,1H), 2.54 (dd, 16.60, 8.43 Hz, 1H), 2.85 (dd, 9.56, 6.92 Hz, 1H), 3.33(m, 1H), 3.95 (s, 3H), 4.60 (m, 2H), 6.66 (d, 7.80 Hz, 1H), 7.04 (t,7.80 Hz, 1H), 7.12 (d, 2.26 Hz, 1H), 7.27 (m, 1H), 8.38 (s, 1H) 146 4 1CF₃COOH 1-[(6-nitro-1H-indol-3-yl)methyl]-4- 302 0.84 (t, 7.17 Hz, 3H),1.28 (m, 4H), propylpyrrolidin-2-one 2.12 (dd, 16.60, 7.80 Hz, 1H), 2.28(m, 1H), 2.58 (dd, 16.60, 8.80 Hz, 1H), 2.90 (dd, 9.56, 6.79 Hz, 1H),3.38 (m, 1H), 4.65 (m, 2H), 7.48 (d, 2.52 Hz, 1H), 7.74 (d, 8.80 Hz,1H), 8.00 (dd, 8.80, 2.01 Hz, 1H), 8.36 (d, 2.01 Hz, 1H), 9.37 (s, 1H)147 4 1 CF₃COOH 4-propyl-1-{[6-(trifluoromethyl)-1H- 325 0.84 (t, 7.04Hz, 3H), 1.27 (m, 4H), indol-3-yl]methyl}pyrrolidin-2-one 2.10 (dd,16.60, 7.92 Hz, 1H), 2.24 (m, 1H), 2.57 (dd, 16.60, 8.55 Hz, 1H), 2.86(dd, 9.56, 6.79 Hz, 1H), 3.34 (dd, 9.31, 7.92 Hz, 1H), 4.63 (m, 2H),7.31 (d, 2.26 Hz, 1H), 7.37 (dd, 8.55, 0.88 Hz, 1H), 7.67 (m, 1H), 7.77(d, 8.55 Hz, 1H), 8.33 (m, 1H) 148 4 1 CF₃COOH1-[(5-nitro-1H-indol-3-yl)methyl]-4- 302 0.85 (t, 7.17 Hz, 3H), 1.29 (m,4H), propylpyrrolidin-2-one 2.19 (dd, 16.60, 7.92 Hz, 1H), 2.33 (m, 1H),2.66 (dd, 16.60, 8.55 Hz, 1H), 2.99 (dd, 9.56, 6.79 Hz, 1H), 3.46 (m,1H), 4.66 (m, 2H), 7.37 (d, 2.01 Hz, 1H), 7.44 (d, 8.80 Hz, 1H), 8.10(dd, 8.80, 2.01 Hz, 1H), 8.61 (d, 2.01 Hz, 1H), 9.22 (s, 1H) 149 4 1CF₃COOH 1-[(7-fluoro-1H-indol-3-yl)methyl]-4- 275 0.84 (t, 7.18 Hz, 3H),1.26 (m, 4H), propylpyrrolidin-2-one 2.10 (dd, 16.37, 7.93 Hz, 1H), 2.24(m, 1H), 2.55 (dd, 16.37, 8.44 Hz, 1H), 2.86 (dd, 9.57, 6.67 Hz, 1H),3.34 (m, 1H), 4.61 (m, 2H), 6.91 (dd, 11.08, 7.81 Hz, 1H), 7.02 (td,7.81, 4.78 Hz, 1H), 7.19 (d, 2.27 Hz, 1H), 7.44 (d, 7.81 Hz, 1H), 8.61(s, 1H) 150 4 1 CF₃COOH 1-[(5-chloro-2-methyl-1H-indol-3- 305/307 0.85(m, 3H), 1.28 (m, 4H), 2.17 (m, 1H), yl)methyl]-4-propylpyrrolidin-2-one2.27 (m, 1H), 2.44 (s, 3H), 2.63 (m, 1H), 2.87 (dd, 9.82, 6.80 Hz, 1H),3.34 (m, 1H), 4.54 (m, 2H), 7.09 (dd, 8.56, 2.01 Hz, 1H), 7.19 (m, 1H),7.50 (m, 1H), 8.05 (s, 1H) 151 4, 1 1-[1H-indol-3-yl(phenyl)methyl]-4-333 0.83 (m, 3H), 1.29 (m, 4H), 2.17 (m, 2H), propylpyrrolidin-2-one2.60 (m, 1H), 2.85 (m, 1H), 3.37 (m, 1H), 6.85 (m, 1H), 6.92 (d, 2.52Hz, 1H), 7.05 (m, 1H), 7.19 (m, 1H), 7.35 (m, 6H), 8.14 (s, 1H) 152 4, 11-[1-(1H-indol-3-yl)propyl]-4- 285 0.86 (t, 7.07 Hz, 3H), 1.02 (t, 7.20Hz, 3H), propylpyrrolidin-2-one 1.25 (m, 6H), 2.01 (m, 1H), 2.22 (m,1H), 2.51 (m, 1H), 2.72 (m, 1H), 3.16 (m, 1H), 5.53 (m, 1H), 7.10 (m,2H), 7.20 (m, 1H), 7.36 (d, 8.08 Hz, 1H), 7.67 (m, 1H), 8.23 (s Hz, 1H)153 4, 1 1-[2-furyl(1H-indol-3-yl)methyl]-4- 323 0.84 (m, 3H), 1.27 (m,4H), 2.13 (m, 2H), propylpyrrolidin-2-one 2.57 (m, 1H), 3.03 (dd, 9.60,6.57 Hz, 1H), 3.30 (dd, 9.60, 7.58 Hz, 1H), 6.32 (d, 2.53 Hz, 1H), 6.38(s, 1H), 7.11 (m, 2H), 7.22 (t, 7.45 Hz, 1H), 7.38 (d, 8.08 Hz, 1H),7.43 (s, 1H), 7.55 (d, 8.08 Hz, 1H), 8.25 (s, 1H) 154 1, 43-[(2-oxo-4-propylpyrrolidin-1- 358 0.87 (m, 3H), 1.31 (m, 4H), 2.16 (m,1H), yl)(phenyl)methyl]-1H-indole-5- 2.34 (m, 1H), 2.64 (m, 1H), 2.83(m, 1H), carbonitrile 3.35 (m, 1H), 6.82 (m, 1H), 7.12 (dd, 10.04, 1.88Hz, 1H), 7.35 (m, 6H), 7.63 (m, 1H), 8.53 (m, 1H) 155 41-(1H-indol-4-ylmethyl)-4- 257 0.83 (t, 7.20 Hz, 3H), 1.26 (m, 4H), 2.12(m, propylpyrrolidin-2-one 1H), 2.24 (m, 1H), 2.57 (dd, 16.17, 8.46 Hz,1H), 2.81 (dd, 9.85, 6.82 Hz, 1H), 3.28 (dd, 9.60, 8.08 Hz, 1H), 4.73(m, 2H), 6.66 (m, 1H), 6.97 (d, 7.07 Hz, 1H), 7.14 (m, 1H), 7.20 (t,2.78 Hz, 1H), 7.36 (d, 8.34 Hz, 1H), 8.55 (s, 1H) 156 41-(1H-indol-7-ylmethyl)-4- 257 0.85 (t, 7.20 Hz, 3H), 1.28 (m, 4H),propylpyrrolidin-2-one 2.09 (dd, 16.67, 8.08 Hz, 1H), 2.28 (m, 1H), 2.53(dd, 16.67, 8.84 Hz, 1H), 2.97 (dd, 9.85, 6.95 Hz, 1H), 3.45 (dd, 9.850,8.84 Hz, 1H), 4.60 (m, 2H), 6.53 (dd, 3.03, 2.15 Hz, 1H), 7.01 (m, 2H),7.24 (m, 1H), 7.61 (d, 7.33 Hz, 1H), 10.02 (s, 1H) 157 41-(isoxazol-4-ylmethyl)-4- 209 (DMSO): 0.86 (t, J 7.15 Hz, 3H),propylpyrrolidin-2-one 1.21-1.36 (m, 4H), 1.95 (dd, J 16.06, 7.53 Hz,1H), 2.27 (m, 1H), 2.38 (dd, J 8.78, 16.06 Hz, 1H), 2.91 (dd, J 9.29,6.78 Hz, 1H), 3.39 (t, J 8.28 Hz, 1H), 4.25 (s, 2H), 8.53 (s, 1H), 8.88(s, 1H) 158 4 1-[(1-phenyl-1H-pyrazol-4- 372 2.56 (dd, J 16.87, 7.55 Hz,1H), 2.86 (dd, J yl)methyl]-4-(2,3,5- 16.87, 8.94 Hz, 1H), 3.36 (dd, J10.8, 14.7 Hz, trifluorophenyl)pyrrolidin-2-one 1H), 3.74-3.86 (m, 2H),4.45 (d, J 14.8 Hz, 1H), 4.51 (d, J 14.8 Hz, 1H), 6.68 (m, 1H), 6.82 (m,1H), 7.29 (t, J 7.5 Hz, 1H), 7.45 (t, J 7.4 Hz, 2H), 7.64-7.69 (m, 3H),7.92 (s, 1H) 159 4 1-[(1-methyl-1H-pyrazol-4- 310 2.52 (dd, J 16.87,7.55 Hz, 1H), 2.84 (dd, J yl)methyl]-4-(2,3,5- 16.87, 9.06 Hz, 1H), 3.30(dd, J 9.57, 6.17 Hz, trifluorophenyl)pyrrolidin-2-one 1H), 3.70-3.82(m, 2H), 3.88 (s, 3H), 4.33 (d, J 14.8 Hz, 1H), 4.43 (d, J 14.8 Hz, 1H),6.64 (m, 1H), 6.83 (m, 1H), 7.35 (s, 1H), 7.41 (s, 1H) 160 41-[(1-benzyl-1H-pyrazol-4- 386 2.51 (dd, J 16.87, 7.30 Hz, 1H), 2.83(dd, J yl)methyl]-4-(2,3,5- 16.87, 9.06 Hz, 1H), 3.28 (dd, J 9.57, 6.29Hz, trifluorophenyl)pyrrolidin-2-one 1H), 3.69 (dd~t, J 9.0 Hz, 1H),3.82 (m, 1H), 4.33 (d, J 15.1 Hz, 1H), 4.43 (d, J 15.1 Hz, 1H), 5.27 (s,2H), 6.64 (m, 1H), 6.83 (m, 1H), 7.20-7.22 (m, 2H), 7.30-7.37 (m, 4H),7.47 (s, 1H) 161 4 4-(2,3,5-trifluorophenyl)-1-[(1,3,5- 338 2.20 (s,3H), 2.22 (s, 3H), 2.52 (dd, J 16.87, trimethyl-1H-pyrazol-4- 7.30 Hz,1H), 2.84 (dd, J 16.87, 9.32 Hz, 1H), yl)methyl]pyrrolidin-2-one 3.19(dd, J 9.82, 6.17 Hz, 1H), 3.60 (t, J 9.1 Hz, 1H), 3.69-3.71 (m, 4H withs at 3.71, 3H), 4.25 (d, J 14.8 Hz, 1H), 4.37 (d, J 14.8 Hz, 1H), 6.60(m, 1H), 6.82 (m, 1H) 162 4 4-phenyl-1-(1H-pyrazol-4- 242 2.58 (dd, J16.67, 8.46 Hz, 1H), 2.84 (dd, J ylmethyl)pyrrolidin-2-one 16.93, 9.09Hz, 1H), 3.33 (dd, J 9.35, 6.95 Hz, 1H), 3.53 (m, 1H), 3.69 (m, 1H),4.45 (s, 2H), 7.17 (d, J 8.3 Hz, 2H), 7.24-7.28 (m, 2H including solventsignal), 7.31 (t, J 7.1 Hz, 2H), 7.56 (s, 2 H) 163 41-({1-[(4-methylphenyl)sulfonyl]-1H- 450 2.43 (s, 3H), 2.56 (dd, J16.87, 7.93 Hz, 1H), pyrazol-4-yl}methyl)-4-(2,3,5- 2.84 (dd, J 16.87,9.19 Hz, 1H), trifluorophenyl)pyrrolidin-2-one 3.28 (dd, J 9.57, 6.80Hz, 1H), 3.68 (t, J 9.1 Hz, 1H), 3.80 (m, 1H), 4.38 (m, 2H), 6.65-6.69(m, 1H), 6.83-6.89 (m, 1H), 7.34 (d, J 8.31 Hz, 2H), 7.66 (s, 1H), 7.89(d, J 8.31 Hz, 2H), 8.04 (s, 1H) 164 41-(1H-pyrazol-4-ylmethyl)-4-(2,3,5- 296 2.55 (dd, J 16.87, 7.55 Hz, 1H),2.86 (dd, J trifluorophenyl)pyrrolidin-2-one 16.87, 8.94 Hz, 1H), 3.31(dd, J 9.32, 6.29 Hz, 1H), 3.68-3.84 (m, 2H), 4.43 (d, J 15.1 Hz, 1H),4.50 (d, J 15.1 Hz, 1H), 6.63-6.65 (m, 1H), 6.79-6.86 (m, 1H), 7.67 (s(broad), 2H), 10.74 (s (broad), 1H) 165 4 1-[(5-chloro-1,3-dimethyl-1H-358/360 2.23 (s, 3H), 2.54 (dd, J 16.93, 7.83 Hz, 1H),pyrazol-4-yl)methyl]-4-(2,3,5- 2.84 (dd, J 16.93, 9.22 Hz, 1H),trifluorophenyl)pyrrolidin-2-one 3.21 (dd, J 9.85, 6.69 Hz, 1H), 3.63(t, J 9.3 Hz, 1H), 3.73-3.81 (m, 4H with s at 3.77 ppm), 4.38 (d, J 15.4Hz, 1H), 4.34 (d, J 15.4 Hz, 1H), 6.66 (m, 1H), 6.83 (m, 1H) 166 41-[(1-chloro-1H-pyrazol-4-yl)methyl]- 330/332 2.53 (dd, J 17.43, 7.71Hz, 1H), 2.86 (dd, J 4-(2,3,5-trifluorophenyl)pyrrolidin-2- 17.18, 9.09Hz, 1H), 3.50 (dd, J 9.60, 6.32 Hz, one 1H), 3.86 (m, 1H), 3.91 (t, J8.59 Hz, 3H), 5.45 (d, J 13.9 Hz, 1H), 4.50 (d, J 13.9 Hz, 1H),6.55-6.60 (m, 1H), 6.80-6.90 (m, 1H), 7.44 (s, 1H), 7.61 (s, 1H) 167 41-[(3,5-dimethyl-1H-pyrazol-4- 324 2.26 (s, 6H), 2.54 (dd, J 16.95, 7.67Hz, 1H), yl)methyl]-4-(2,3,5- 2.85 (dd, J 16.55, 9.08 Hz, 1H),trifluorophenyl)pyrrolidin-2-one 3.19 (dd, J 9.69, 6.46 Hz, 1H), 3.61(t, J 9.3 Hz, 1H), 3.72-3.79 (m, 1H), 4.31 (d, J 14.1 Hz, 1H), 4.38 (d,J 14.1 Hz, 1H), 6.60-6.65 (d, J 6.86 Hz, 1H), 6.80-6.85 (m, 1H) 168 41-[(3-methyl-1H-pyrazol-4- 310 2.31 (s, 3H), 2.54 (dd, J 16.87, 7.55 Hz,1H), yl)methyl]-4-(2,3,5- 2.85 (dd, J 16.87, 9.06 Hz, 1H),trifluorophenyl)pyrrolidin-2-one 3.25 (dd, J 9.57, 6.42 Hz, 1H), 3.67(t, J 8.8 Hz, 1H), 3.72-3.83 (m, 1H), 4.35 (d, J 14.9 Hz, 1H), 4.43 (d,J 14.9 Hz, 1H), 6.60-6.65 (m, 1H), 6.80-6.85 (m, 1H), 7.46 (s, 1H) 169 41-[(5-amino-1,3-dimethyl-1H- 339 2.15 (s, 3H), 2.50 (dd, J 16.93, 7.07Hz, 1H), pyrazol-4-yl)methyl]-4-(2,3,5- 2.83 (dd, J 16.93, 8.84 Hz, 1H),trifluorophenyl)pyrrolidin-2-one 3.35 (dd, J 9.35, 5.68 Hz, 1H), 3.58(s, 3H), 3.74-3.86 (m, 2H), 4.12 (d, J 15.4 Hz, 1H), 4.22-4.25 (m, 3H),6.60-6.65 (m, 1H), 6.80-6.85 (m, 1H) 170 4 1 CF₃COOH1-[(5-amino-1-methyl-1H-pyrazol-4- 237 (D2O): 0.81 (t, J 7.20 Hz, 3H),1.13-1.27 (m, yl)methyl]-4-propylpyrrolidin-2-one 2H), 1.26-1.35 (m,2H), 2.11 (dd, J 17.18, 6.95 Hz, 1H), 2.35 (m, 1H), 2.56 (dd, J 16.93,8.84 Hz, 1H), 3.01 (dd, J 10.11, 6.06 Hz, 1H), 3.47 (dd, J 10.11, 8.08Hz, 1H), 3.65 (s, 3H), 4.15 (d, J 15.6 Hz, 1H), 4.24 (d, J 15.6 Hz, 1H),7.59 (s, 1H) 171 A-4§ (−)-1-(1H-pyrazol-4-ylmethyl)-4- 296 2.55 (dd, J16.81, 7.65 Hz, 1H), 2.86 (dd, J (2,3,5-trifluorophenyl)pyrrolidin-2-16.81, 8.91 Hz, 1H), 3.31 (dd, J 9.54, 6.27 Hz, one 1H), 3.70-3.85 (m,2H), 4.42 (d, J 14.8 Hz, 1H), 4.50 (d, J 14.8 Hz, 1H), 6.60-6.70 (m,1H), 6.80-6.85 (m, 1H), 7.57 (s, 2H), 11.02 (s (broad), 1H) 172 B-4§(+)-1-(1H-pyrazol-4-ylmethyl)-4- 296 2.55 (dd, J 16.81, 7.65 Hz, 1H),2.86 (dd, J (2,3,5-trifluorophenyl)pyrrolidin-2- 16.81, 8.91 Hz, 1H),3.31 (dd, J 9.54, 6.27 Hz, one 1H), 3.70-3.85 (m, 2H), 4.42 (d, J 14.8Hz, 1H), 4.50 (d, J 14.8 Hz, 1H), 6.60-6.70 (m, 1H), 6.80-6.85 (m, 1H),7.57 (s, 2H), 11.12 (s (broad), 1H) 173 1 H₂O1-(1H-pyrazol-4-ylmethyl)-1,3- 214 (DMSO): 3.58 (s, 2H), 4.74 (s, 2H),6.99 (t, dihydro-2H-indol-2-one J 7.1 Hz, 1H), 7.05 (d, J 7.58 Hz, 1H),7.20-7.27 (m, 2H), 7.47 (s (broad), 1H), 7.70 (s (broad), 1H), 7.90 (s(broad), 1H), 12.71 (m, 1H) 174 5-chloro-1-(1H-pyrazol-4-ylmethyl)-248/250 (DMSO): 3.64 (s, 2H), 4.86 (s, 2H), 6.96 (d,1,3-dihydro-2H-indol-2-one J 8.28 Hz, 1H), 7.29 (d, J 8.53 Hz, 1H), 7.32(s, 1H), 7.61 (s (broad), 2H), 12.66 (m, 1H) 175 5-chloro-1-({1-[(4-402/404 (DMSO): 2.38 (s, 3H), 3.62 (s, 2H), 4.74 (s,methylphenyl)sulfonyl]-1H-pyrazol- 2H), 6.96 (d, J 8.28 Hz, 1H), 7.26(d, J 8.56 Hz, 4-yl}methyl)-1,3-dihydro-2H-indol-2- 1H), 7.33 (s, 1H),7.45 (d, J 8.0 Hz, 2H), one 7.77-7.83 (m, 3H), 8.46 (s, 1H) 176 41-{[5-chloro-1-methyl-3- 324/326 0.89 (t, J 7.3 Hz, 3H), 1.33 (m, 4H),(trifluoromethyl)-1H-pyrazol-4- 2.11 (dd, J 16.6, 8.1 Hz, 1H), 2.30 (m,1H), yl]methyl}-4-propylpyrrolidin-2-one 2.57 (dd, J 16.9, 8.8 Hz, 1H),2.82 (dd, J 9.6, 7.1 Hz, 1H), 3.29 (m, 1H), 3.90 (s, 3H), 4.45 (q, J15.1 Hz, 2H) 177 4 2 CF₃COOH 1-[(5-amino-1H-pyrazol-4-yl)methyl]- 311(DMSO-CDCl₃): 2.61 (dd, J 17.0, 7.7 Hz, 1H),4-(2,3,5-trifluorophenyl)pyrrolidin-2- 2.91 (dd, J 17.0, 8.7 Hz, 1H),3.40 (dd, J one 9.2, 6.7 Hz, 1H), 3.75-3.92 (m, 2H), 4.28-4.35 (m, 2Hoverlapped with solvent signal), 6.63-6.65 (m, 1H), 6.79-6.86 (m, 1H),7.26 (m, 1H overlapped with solvent signal), 7.46 (s, 2H) 178 4 1CF₃COOH 1-[(1-benzyl-5-chloro-1H-pyrazol-4- 332/334 0.89 (t, J 7.3 Hz,3H), 1.32 (m, 4H), yl)methyl]-4-propylpyrrolidin-2-one 2.07 (dd, J16.56, 7.78 Hz, 1H), 2.29 (m, 1H), 2.52 (dd, J 16.56, 8.66 Hz, 1H), 2.87(dd, J 9.54, 6.78 Hz, 1H), 3.34 (m, 1H), 4.30 (s, 2H), 5.32 (s, 2H),7.21 (d, J 7.03 Hz, 2H), 7.28-7.37 (m, 3H), 7.51 (s, 1H) 179 41-[(1,3-dimethyl-1H-pyrazol-5- 324 2.22 (s, 3H), 2.58 (dd, J 16.93, 8.08Hz, 1H), yl)methyl]-4-(2,3,5- 2.86 (dd, J 17.18, 9.22 Hz, 1H),trifluorophenyl)pyrrolidin-2-one 3.27 (dd, J 9.60, 6.82 Hz, 1H),3.60-3.70 (m, 1H), 3.79 (m, 4H), 4.47 (d, J 15.4 Hz, 1H), 4.52 (d, J15.4 Hz, 1H), 5.95 (s, 1H), 6.60-6.70 (m, 1H), 6.80-6.90 (m, 1H) 180 41-({1-[(4-methylphenyl)sulfonyl]-1H- 450 pyrazol-5-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 181 41-(1H-pyrazol-5-ylmethyl)-4-(2,3,5- 296 2.55 (dd, J 16.8, 7.3 Hz, 1H),2.88 (dd, J trifluorophenyl)pyrrolidin-2-one 16.8, 8.97 Hz, 1H), 3.39(dd, J 5.7, 9.3 Hz, 1H), 3.76-3.86 (m, 2H), 4.53 (d, J 14.9 Hz, 1H),4.63 (d, J 14.9 Hz, 1H), 6.28 (d, J 2.0 Hz, 1H), 6.68-6.70 (m, 1H),6.80-6.84 (m, 1H), 7.55 (d, J 2.0 Hz, 1H) 182 41-[(4-bromo-1-methyl-1H-pyrazol-5- 388/390 2.56 (dd, J 16.93, 7.71 Hz,1H), 2.86 (dd, J yl)methyl]-4-(2,3,5- 17.18, 8.84 Hz, 1H), 3.31 (dd, J9.60, 6.44 Hz, trifluorophenyl)pyrrolidin-2-one 1H), 3.71-3.82 (m, 2H),3.93 (s, 3H), 4.55 (d, J 15.4 Hz, 1H), 4.63 (d, J 15.4 Hz, 1H),6.60-6.70 (m, 1H), 6.80-90 (m, 1H), 7.44 (s, 1H) 183 41-[(1-methyl-1H-pyrazol-5- 2.59 (dd, J 17.12, 7.93 Hz, 1H), 2.87 (dd, Jyl)methyl]-4-(2,3,5- 17.12, 9.19 Hz, 1H), 3.27 (dd, J 9.82, 6.67 Hz,trifluorophenyl)pyrrolidin-2-one 1H), 3.67 (dd~t, J 9.31 Hz, 1H), 3.78(m, 1H), 3.87 (s, 3H), 4.54 (d, J 15.4 Hz, 1H), 4.61 (d, J 15.4 Hz, 1H),6.18 (d, J 1.76 Hz, 1H), 6.64 (m, 1H), 6.85 (m, 1H), 7.42 (d, J 1.76 Hz,1H) 184 4 1-[(6-bromo-2-methylpyrazolo[1,5- 351/353 0.86 (t, 7.20 Hz,3H), 1.30 (m, 4H), a]pyrimidin-3-yl)methyl]-4- 2.07 (dd, 16.67, 7.83 Hz,1H), 2.25 (m, 1H), propylpyrrolidin-2-one 2.51 (m, 4H), 2.87 (dd, 9.60,6.82 Hz, 1H), 3.36 (dd, 9.60, 7.96 Hz, 1H), 4.64 (m, 2H), 8.40 (d, 2.27Hz, 1H), 8.68 (d, 2.27 Hz, 1H) 185 4 1-[(2-methylpyrazolo[1,5- 273 0.86(t, 7.20 Hz, 3H), 1.29 (m, 4H), a]pyrimidin-3-yl)methyl]-4- 2.07 (dd,16.67, 7.96 Hz, 1H), 2.25 (m, 1H), propylpyrrolidin-2-one 2.52 (m, 4H),2.89 (dd, 9.60, 6.82 Hz, 1H), 3.37 (m, 1H), 4.67 (m, 2H), 6.75 (dd,6.82, 4.04 Hz, 1H), 8.43 (dd, 3.79, 1.64 Hz, 1H), 8.56 (m, 1H) 186 41-[(6-bromo-2-phenylpyrazolo[1,5- 413/415 0.81 (m, 3H), 1.18 (m, 4H),1.98 (dd, 16.37, a]pyrimidin-3-yl)methyl]-4- 7.81 Hz, 1H), 2.11 (m, 1H),2.45 (dd, 16.56, propylpyrrolidin-2-one 8.53 Hz, 1H), 2.74 (dd, 9.54,6.65 Hz, 1H), 3.22 (m, 1H), 4.91 (s, 2H), 7.46 (m, 3H), 7.79 (m, 2H),8.47 (d, 2.01 Hz, 1H), 8.82 (d, 2.01 Hz, 1H) 187 41-[(6-bromo-2-thien-2- 419/421 0.83 (t, 7.30 Hz, 3H), 1.24 (m, 4H), 2.08(m, ylpyrazolo[1,5-a]pyrimidin-3- 1H), 2.21 (m, 1H), 2.54 (dd, 16.62,8.44 Hz, yl)methyl]-4-propylpyrrolidin-2-one 1H), 2.80 (dd, 9.57, 6.67Hz, 1H), 3.27 (m, 1H), 4.93 (m, 2H), 7.18 (m, 1H), 7.42 (d, 5.04 Hz,1H), 7.76 (d, 3.78 Hz, 1H), 8.46 (d, 2.01 Hz, 1H), 8.78 (d, 2.01 Hz, 1H)188 4 4-propyl-1-[(2-thien-2- 341 0.82 (m, 3H), 1.24 (m, 4H), 1.71 (s,1H), ylpyrazolo[1,5-a]pyrimidin-3- 2.14 (m, 2H), 2.54 (dd, 16.31, 8.53Hz, 1H), yl)methyl]pyrrolidin-2-one 2.82 (dd, 9.79, 6.78 Hz, 1H), 3.29(m, 1H), 4.96 (m, 2H), 7.18 (m, 1H), 7.41 (m, 1H), 7.76 (m, 1H), 8.48(dd, 4.02, 1.76 Hz, 1H), 8.66 (dd, 7.03, 1.51 Hz, 1H) 189 41-[(6-bromo-2- 377/379 0.84 (m, 3H), 1.01 (m, 4H), 1.28 (m, 4H),cyclopropylpyrazolo[1,5-a]pyrimidin- 2.17 (m, 3H), 2.55 (m, 1H), 2.87(m, 1H), 3-yl)methyl]-4-propylpyrrolidin-2-one 3.35 (m, 1H), 4.72 (s,2H), 8.36 (m, 1H), 8.61 (m, 1H) 190 41-[(6-bromo-2-tert-butylpyrazolo[1,5- 393/395 0.96 (t, 7.05 Hz, 3H),1.38 (m, 4H), 1.54 (s, a]pyrimidin-3-yl)methyl]-4- 9H), 2.20 (dd, 16.37,8.06 Hz, 1H), 2.32 (m, propylpyrrolidin-2-one 1H), 2.65 (dd, 16.37, 8.56Hz, 1H), 2.87 (dd, 9.82, 6.92 Hz, 1H), 3.33 (m, 1H), 4.94 (m, 2H), 8.51(d, 2.01 Hz, 1H), 8.83 (d, 2.01 Hz, 1H) 191 4 1-[(2-phenylpyrazolo[1,5-335 0.81 (m, 3H), 1.18 (s, 4H), 1.96 (m, 1H),a]pyrimidin-3-yl)methyl]-4- 2.09 (m, 1H), 2.45 (dd, 16.31, 8.53 Hz, 1H),propylpyrrolidin-2-one 2.75 (m, 1H), 3.23 (m, 1H), 4.94 (s, 2H), 6.85(m, 1H), 7.47 (m, 3H), 7.81 (d, 7.53 Hz, 2H), 8.50 (s, 1H), 8.69 (d,7.03 Hz, 1H) 192 4 1-[(2-tert-butyl-6- 355 0.72 (m, 2H), 0.84 (m, 3H),1.04 (m, 2H), cyclopropylpyrazolo[1,5-a]pyrimidin- 1.26 (m, 4H), 1.43(m, 9H), 1.93 (m, 1H), 3-yl)methyl]-4-propylpyrrolidin-2-one 2.16 (m,2H), 2.53 (m, 1H), 2.77 (m, 1H), 3.22 (m, 1H), 4.84 (m, 2H), 8.32 (m,2H) 193 4 1-{[2-(2-furyl)pyrazolo[1,5- 325 0.82 (t, 7.15 Hz, 3H), 1.25(m, 4H), 2.09 (m, a]pyrimidin-3-yl]methyl}-4- 1H), 2.20 (m, 1H), 2.54(dd, 16.56, 8.41 Hz, propylpyrrolidin-2-one 1H), 2.82 (dd, 9.79, 6.78Hz, 1H), 3.29 (dd, 9.54, 7.91 Hz, 1H), 4.95 (m, 2H), 6.57 (dd, 3.26,1.88 Hz, 1H), 6.85 (dd, 7.03, 4.02 Hz, 1H), 7.21 (d, 3.26 Hz, 1H), 7.59(d, 1.25 Hz, 1H), 8.50 (dd, 4.02, 1.76 Hz, 1H), 8.68 (dd, 7.03, 1.76 Hz,1H) 194 4 1-[(2-methyl-6-thien-2- 355 0.86 (t, 7.18 Hz, 3H), 1.30 (m,4H), ylpyrazolo[1,5-a]pyrimidin-3- 2.08 (dd, 16.56, 7.78 Hz, 1H), 2.26(m, 1H), yl)methyl]-4-propylpyrrolidin-2-one 2.53 (m, 4H), 2.91 (dd,9.79, 6.78 Hz, 1H), 3.40 (dd, 9.54, 8.03 Hz, 1H), 4.68 (m, 2H), 7.15 (m,1H), 7.32 (d, 3.51 Hz, 1H), 7.38 (d, 5.02 Hz, 1H), 8.68 (m, 1H), 8.73(m, 1H) 195 4 1-[(2-methyl-6-phenylpyrazolo[1,5- 349 0.87 (t, 7.15 Hz,3H), 1.32 (m, 4H), a]pyrimidin-3-yl)methyl]-4- 2.09 (dd, 16.62, 7.93 Hz,1H), 2.27 (m, 1H), propylpyrrolidin-2-one 2.53 (m, 4H), 2.93 (dd, 9.79,6.78 Hz, 1H), 3.41 (dd, 9.54, 8.03 Hz, 1H), 4.70 (m, 2H), 7.50 (m, 5H),8.71 (m, 2H) 196 4 1-{[2-methyl-6-(1H-pyrrol-2- 338 0.85 (t, 7.05 Hz,3H), 1.28 (m, 4H), yl)pyrazolo[1,5-a]pyrimidin-3- 2.10 (dd, 16.62, 7.81Hz, 1H), 2.27 (m, 1H), yl]methyl}-4-propylpyrrolidin-2-one 2.42 (s, 3H),2.54 (dd, 16.56, 8.53 Hz, 1H), 2.93 (dd, 9.82, 6.80 Hz, 1H), 3.41 (m,1H), 4.64 (m, 2H), 6.31 (m, 1H), 6.54 (m, 1H), 6.92 (m, 1H), 8.67 (m,1H), 8.76 (m, 1H), 10.27 (m, 1H) 197 4 1-({6-[(1E)-hex-1-enyl]-2- 3550.86 (t, J 7.3 Hz, 3H), 0.94 (t, J 7.3 Hz, 3H),methylpyrazolo[1,5-a]pyrimidin-3- 1.35 (m, 8H), 2.07 (dd, J 16.4, 7.8Hz, 1H), yl}methyl)-4-propylpyrrolidin-2-one 2.24 (m, 3H), 2.52 (m, 4H),2.88 (m, 1H), 3.36 (m, 1H), 4.65 (m, 2H), 6.29 (s, 2H), 8.39 (s, 1H),8.54 (s, 1H) 198 4 1-[(6-chloro-2-phenylpyrazolo[1,5- 369/371 0.80 (s,3H), 1.17 (m, 4H), 2.03 (m, 2H), a]pyrimidin-3-yl)methyl]-4- 2.45 (dd,16.11, 8.31 Hz, 1H), 2.74 (m, 1H), propylpyrrolidin-2-one 3.21 (t, 8.31Hz, 1H), 4.91 (s, 2H), 7.44 (m, 3H), 7.79 (m, 2H), 8.42 (s, 1H), 8.73(s, 1H) 199 4 1-{[2-methyl-6- 373 0.87 (m, 3H), 1.30 (m, 4H), 2.07 (m,1H), (phenylethynyl)pyrazolo[1,5- 2.26 (m, 1H), 2.53 (m, 4H), 2.90 (dd,9.57, a]pyrimidin-3-yl]methyl}-4- 6.80 Hz, 1H), 3.38 (m, 1H), 4.66 (m,2H), propylpyrrolidin-2-one 7.39 (m, 3H), 7.56 (m, 2H), 8.50 (d, 1.51Hz, 1H), 8.69 (d, 1.76 Hz, 1H) 200 4 1-[(6-bromo-2-phenylpyrazolo[1,5-433/435 2.09 (dd, 16.81, 7.78 Hz, 1H), 2.56 (dd,a]pyrimidin-3-yl)methyl]-4-(2,2- 16.56, 8.53 Hz, 1H), 2.91 (m, 2H), 3.33(m, difluorovinyl)pyrrolidin-2-one 1H), 3.94 (ddd, 24.6, 9.54, 2.0 Hz,1H), 4.93 (m, 2H), 7.48 (m, 3H), 7.79 (m, 2H), 8.48 (d, 2.26 Hz, 1H),8.82 (d, 2.01 Hz, 1H) 201 4 1-[(6-hydroxy-2-methylpyrazolo[1,5- 289 0.84(t, 7.15 Hz, 3H), 1.28 (m, 4H), 2.13 (m, a]pyrimidin-3-yl)methyl]-4-1H), 2.29 (m, 1H), 2.48 (s, 3H), 2.59 (dd, propylpyrrolidin-2-one 16.56,8.53 Hz, 1H), 2.92 (dd, 9.54, 7.03 Hz, 1H), 3.39 (t, 8.91 Hz, 1H), 4.70(m, 2H), 8.23 (d, 1.76 Hz, 1H), 9.01 (d, 2.01 Hz, 1H), 10.56 (m, 1H) 2024 1-[(6-methyl-2-phenylpyrazolo[1,5- 349 0.80 (t, 6.02 Hz, 3H), 1.17 (m,4H), 1.97 (m, a]pyrimidin-3-yl)methyl]-4- 1H), 2.09 (m, 1H), 2.44 (m,4H), 2.74 (dd, propylpyrrolidin-2-one 9.54, 6.69 Hz, 1H), 3.22 (m, 1H),4.91 (s, 2H), 7.41 (m, 1H), 7.48 (m, 2H), 7.79 (m, 2H), 8.37 (m, 1H),8.47 (m, 1H) 203 4 4-(2,2-difluorovinyl)-1-[(2- 355 0.81 (t, 6.69 Hz,3H), 1.19 (m, 4H), 1.97 (m, phenylpyrazolo[1,5-a]pyrimidin-3- 1H), 2.13(m, 1H), 2.47 (dd, 16.32, 8.53 Hz, yl)methyl]pyrrolidin-2-one 1H), 2.78(dd, 9.54, 6.69 Hz, 1H), 3.27 (t, 8.89 Hz, 1H), 4.91 (m, 2H), 6.86 (m,1H), 7.18 (t, 8.53 Hz, 2H), 7.83 (dd, 8.07, 5.50 Hz, 2H), 8.50 (d, 4.03Hz, 1H), 8.67 (d, 6.79 Hz, 1H) 204 4 1-[(6-methoxy-2-phenylpyrazolo[1,5-365 0.80 (m, 3H), 1.16 (m, 4H), 1.94 (m, 1H),a]pyrimidin-3-yl)methyl]-4- 2.14 (m, 1H), 2.45 (dd, J 16.3, 8.4 Hz, 1H),propylpyrrolidin-2-one 2.74 (dd, J 9.2, 6.8 Hz, 1H), 3.22 (m, 1H), 3.90(s, 3H), 4.90 (s, 2H), 7.40 (m, 1H), 7.47 (m, 2H), 7.78 (d, J 8.1 Hz,2H), 8.24 (d, J 1.5 Hz, 1H), 8.38 (s, 1H) 205 4 1 C₂H₂O₄1-[(5-chloropyrazolo[1,5-a]pyrimidin- 293/295 0.88 (t, 7.06 Hz, 3H),1.32 (m, 4H), 3-yl)methyl]-4-propylpyrrolidin-2-one 2.10 (dd, 16.32,7.70 Hz, 1H), 2.31 (m, 1H), 2.55 (dd, 16.51, 8.80 Hz, 1H), 2.99 (m, 1H),3.46 (m, 1H), 4.63 (s, 2H), 6.80 (d, 7.15 Hz, 1H), 8.13 (m, 1H), 8.54(d, 7.15 Hz, 1H) 206 4 4-(2,2-difluorovinyl)-1-[(5,6-dimethyl- 383 2.10(dd, 16.56, 7.53 Hz, 1H), 2.32 (s, 3H),2-phenylpyrazolo[1,5-a]pyrimidin-3- 2.55 (m, 4H), 2.89 (m, 2H), 3.34 (m,1H), yl)methyl]pyrrolidin-2-one 3.94 (m, 1H), 4.91 (m, 2H), 7.44 (m,3H), 7.77 (d, 7.28 Hz, 2H), 8.36 (s, 1H) 207 44-(2,2-difluorovinyl)-1-[(6-fluoro-5- 387 2.10 (dd, 16.56, 7.53 Hz, 1H),2.56 (dd, methyl-2-phenylpyrazolo[1,5- 16.56, 8.53 Hz, 1H), 2.64 (d,3.01 Hz, 3H), a]pyrimidin-3-yl)methyl]pyrrolidin-2- 2.89 (m, 2H), 3.33(m, 1H), 3.94 (m, 1H), one 4.91 (m, 2H), 7.47 (m, 3H), 7.76 (m, 2H),8.52 (d, 4.27 Hz, 1H) 208 4 1-[(5-methoxypyrazolo[1,5- 289 0.88 (t, 7.15Hz, 3H), 1.31 (m, 4H), a]pyrimidin-3-yl)methyl]-4- 2.07 (dd, 16.56, 7.78Hz, 1H), 2.28 (m, 1H), propylpyrrolidin-2-one 2.53 (dd, 16.56, 8.78 Hz,1H), 2.95 (dd, 9.54, 6.90 Hz, 1H), 3.44 (dd, 9.79, 8.16 Hz, 1H), 4.01(s, 3H), 4.56 (s, 2H), 6.32 (d, 7.28 Hz, 1H), 7.93 (s, 1H), 8.37 (d,7.28 Hz, 1H) 209 4 1-{[2-(4-bromophenyl)pyrazolo[1,5- 433/435 2.24 (dd,17.07, 7.65 Hz, 1H), 2.69 (dd, a]pyrimidin-3-yl]methyl}-4-(2,2- 17.07,8.53 Hz, 1H), 3.01 (m, 2H), 3.45 (m, difluorovinyl)pyrrolidin-2-one 1H),4.02 (m, 1H), 4.94 (s, 2H), 6.92 (dd, 7.03, 4.02 Hz, 1H), 7.66 (m, 4H),8.54 (d, 3.51 Hz, 1H), 8.73 (d, 7.03 Hz, 1H) 210 41-{[2-(4-fluorophenyl)pyrazolo[1,5- 353 0.82 (m, 3H), 1.19 (m, 4H), 1.98(m, 1H), a]pyrimidin-3-yl]methyl}-4- 2.13 (m, 1H), 2.47 (dd, J 16.3, 8.4Hz, 1H), propylpyrrolidin-2-one 2.78 (dd, J 9.5, 6.6 Hz, 1H), 3.27 (t, J9.0 Hz, 1H), 4.91 (s, 2H), 6.87 (m, 1H), 7.18 (t, J 8.4 Hz, 2H), 7.83(dd, J 8.1, 5.5 Hz, 2H), 8.48 (d, J 4.0 Hz, 1H), 8.67 (d, J 6.8 Hz, 1H)211 4 4-(2,2-difluorovinyl)-1-[(6-methyl-2- 369 2.09 (m, 1H), 2.41 (s,3H), 2.56 (dd, 16.81, phenylpyrazolo[1,5-a]pyrimidin-3- 8.53 Hz, 1H),2.90 (m, 2H), 3.34 (m, 1H), yl)methyl]pyrrolidin-2-one 3.94 (m, 1H),4.93 (m, 2H), 7.45 (m, 3H), 7.78 (d, 7.28 Hz, 2H), 8.37 (m, 1H), 8.48(m, 1H) 212 4 4-(2,2-difluorovinyl)-1-[(5-methyl-2- 369 2.09 (dd, 16.69,7.52 Hz, 1H), 2.55 (dd, phenylpyrazolo[1,5-a]pyrimidin-3- 16.69, 8.44Hz, 1H), 2.62 (s, 3H), 2.90 (m, yl)methyl]pyrrolidin-2-one 2H), 3.35 (m,1H), 3.94 (m, 1H), 4.92 (m, 2H), 6.70 (d, 6.97 Hz, 1H), 7.46 (m, 3H),7.78 (m, 2H), 8.52 (d, 7.15 Hz, 1H) 213 44-(2,2-difluorovinyl)-1-[(2-thien-2- 361 2.23 (dd, 16.69, 7.79 Hz, 1H),2.66 (dd, ylpyrazolo[1,5-a]pyrimidin-3- 16.69, 8.71 Hz, 1H), 3.00 (m,2H), 3.41 (dd, yl)methyl]pyrrolidin-2-one 9.54, 7.78 Hz, 1H), 4.07 (m,1H), 4.98 (m, 2H), 6.85 (dd, 6.97, 4.03 Hz, 1H), 7.19 (m, 1H), 7.43 (d,5.14 Hz, 1H), 7.75 (d, 3.67 Hz, 1H), 8.48 (dd, 3.85, 1.47 Hz, 1H), 8.66(m, 1H) 214 4 1-{[2-(4-chlorophenyl)-6- 383/385 0.81 (m, 3H), 1.19 (m,4H), 2.01 (m, 1H), methylpyrazolo[1,5-a]pyrimidin-3- 2.13 (m, 1H), 2.46(m, 4H), 2.77 (dd, 9.72, yl]methyl}-4-propylpyrrolidin-2-one 6.69 Hz,1H), 3.25 (m, 1H), 4.89 (s, 2H), 7.45 (d, 8.62 Hz, 2H), 7.77 (d, 8.62Hz, 2H), 8.38 (m, 1H), 8.46 (m, 1H) 215 41-{[2-(4-chlorophenyl)pyrazolo[1,5- 389/391 2.24 (dd, 16.87, 7.70 Hz,1H), 2.69 (dd, a]pyrimidin-3-yl]methyl}-4-(2,2- 17.06, 8.62 Hz, 1H),2.99 (m, 2H), 3.45 (m, difluorovinyl)pyrrolidin-2-one 1H), 4.02 (m, 1H),4.94 (s, 2H), 6.92 (dd, 7.15, 4.13 Hz, 1H), 7.48 (d, 8.44 Hz, 2H), 7.75(d, 8.40 Hz, 2H), 8.54 (dd, 4.03, 1.65 Hz, 1H), 8.72 (dd, 6.97, 1.65 Hz,1H) 216 4 1-[(6-chloro-2-phenylpyrazolo[1,5- 389/391 2.11 (dd, 16.69,7.70 Hz, 1H), 2.56 (dd, a]pyrimidin-3-yl)methyl]-4-(2,2- 16.51, 8.53 Hz,1H), 2.89 (m, 2H), 3.33 (m, difluorovinyl)pyrrolidin-2-one 1H), 3.94 (m,1H), 4.93 (m, 2H), 7.49 (m, 3H), 7.78 (m, 2H), 8.43 (d, 2.20 Hz, 1H),8.72 (d, 2.20 Hz, 1H) 217 4 1-{[6-chloro-2-(4- 423/425/427 2.15 (dd,16.69, 7.70 Hz, 1H), 2.59 (dd, chlorophenyl)pyrazolo[1,5- 16.69, 8.62Hz, 1H), 2.95 (m, 2H), 3.38 (m, a]pyrimidin-3-yl]methyl}-4-(2,2- 1H),4.01 (m, 1H), 4.90 (s, 2H), 7.48 (d, difluorovinyl)pyrrolidin-2-one 8.44Hz, 2H), 7.78 (d, 8.44 Hz, 2H), 8.44 (d, 2.20 Hz, 1H), 8.71 (d, 2.38 Hz,1H) 218 4 1-[(2-cyclopropyl-5- 333 1.03 (m, 4H), 2.20 (m, 2H), 2.56 (sHz, 3H), methylpyrazolo[1,5-a]pyrimidin-3- 2.65 (dd, 16.51, 8.71 Hz,1H), 3.01 (m, 1H), yl)methyl]-4-(2,2- 3.10 (m, 1H), 3.48 (m, 1H), 4.18(m, 1H), difluorovinyl)pyrrolidin-2-one 4.75 (s, 2H), 6.56 (d, 7.15 Hz,1H), 8.34 (d, 7.15 Hz, 1H) 219 4 1-[(5-chloro-2- 353/355 1.04 (m, 4H),2.21 (m, 2H), 2.65 (dd, 16.81, cyclopropylpyrazolo[1,5-a]pyrimidin- 8.66Hz, 1H), 3.03 (m, 1H), 3.12 (m, 1H), 3-yl)methyl]-4-(2,2- 3.49 (m, 1H),4.20 (m, 1H), 4.73 (s Hz, 2H), difluorovinyl)pyrrolidin-2-one 6.68 (d,7.28 Hz, 1H), 8.38 (d, 7.28 Hz, 1H) 220 4 1-[(5-chloro-2,6- 341/343 2.22(dd, 16.56, 8.03 Hz, 1H), 2.36 (d, 0.50 Hz,dimethylpyrazolo[1,5-a]pyrimidin-3- 3H), 2.47 (s, 3H), 2.64 (m, 1H),yl)methyl]-4-(2,2- 3.08 (m, 2H), 3.49 (m, 1H), 4.19 (m, 1H),difluorovinyl)pyrrolidin-2-one 4.61 (s, 2H), 8.35 (d, 0.75 Hz, 1H) 221 41-[(5-bromo-1H-pyrazolo[3,4- 357/359 (DMSO) 2.19 (dd, 16.28, 8.14 Hz,1H), b]pyridin-3-yl)methyl]-4-(2,2- 2.53 (m, 1H), 3.08 (m, 2H), 3.48 (m,1H), difluorovinyl)pyrrolidin-2-one 4.66 (m, 2H), 8.41 (d, 2.03 Hz, 1H),8.60 (d, 2.03 Hz, 1H), 13.76 (s, 1H) 2221-(pyridazin-4-ylmethyl)pyrrolidin-2- (DMSO): 1.95 (quint, J 7.79 Hz,2H), 2.29 (t, one J 8.22 Hz, 2H), 3.28 (t, J 7.10 Hz, 2H), 4.42 (s, 2H),7.44-7.48 (m, 1H), 9.08 (m, 1H), 9.12 (dd, J 1.15, 4.12 Hz, 1H). 2231-[(1-oxidopyridin-2- 193 2.20 (m, 2H), 2.40 (t, J 8.0 Hz, 2H), 3.55 (t,yl)methyl]pyrrolidin-2-one J 8.0 Hz, 2H), 4.70 (s, 2H), 7.15-7.35 (m, 3Hoverlapped with solvent signal), 8.25 (d, J 7.40 Hz, 1H) 224 4 1 HCl4-propyl-1-(pyridin-3- 219 (DMSO): 0.79 (t, J 7.0 Hz, 3H),ylmethyl)pyrrolidin-2-one 1.18-1.33 (m, 4H), 2.03 (dd, J 11.2, 8.7 Hz,1H), 2.39-2.50 (m, 2H), 2.99 (dd ~= t, J 10.8 Hz, 1H), 3.43 (t, J 10.8Hz, 1H), 4.48 (d, J 15.7 Hz, 1H), 4.61 (d, J 15.7 Hz, 1H), 8.01 (m, 1H),8.40 (d, J 8.29 Hz, 1H), 8.68-8.73 (m, 2H) 225 A-1§(+)-1-(1-pyridin-3-ylpropyl)pyrrolidin- 0.96 (t, J 7.32 Hz, 3H), 1.96(m, 4H), 2-one 2.41 (m, 2H), 3.02 (m, 1H), 3.33 (m, 1H), 5.23 (dd, J9.23, 6.75 Hz, 1H), 7.26 (m, 1H), 7.63 (m, 1H), 8.50-8.60 (m, 2H) 226B-1§ (−)-1-(1-pyridin-3-ylpropyl)pyrrolidin- (204) 0.96 (t, J 7.32 Hz,3H), 1.96 (m, 4H), 2-one 2.41 (m, 2H), 3.02 (m, 1H), 3.33 (m, 1H), 5.23(dd, J 9.23, 6.75 Hz, 1H), 7.26 (m, 1H), 7.63 (m, 1H), 8.50-8.60 (m, 2H)227 5-chloro-1-[(2-fluoropyridin-3- (DMSO): 3.77 (s, 2H), 4.49 (s, 2H),6.97 (d, J yl)methyl]-1,3-dihydro-2H-indol-2- 8.39 Hz, 1H), 7.31-7.39(m, 2H), 7.44 (d, J 2 Hz, one 1H), 7.82 (t, J 8.09 Hz, 1H), 8.21 (d, J4.72 Hz, 1H) 228 4 1-[(6-chloropyridin-3-yl)methyl]-4- 253/255 (DMSO):0.86 (t, J 7.3 Hz, 3H), 1.30 (m, 4H), propylpyrrolidin-2-one 2.01 (dd, J16.2, 7.6 Hz, 1H), 2.29 (m, 1H), 2.43 (m, 1H), 2.89 (dd, J 9.3, 6.6 Hz,1H), 3.37 (m, 1H), 4.39 (s, 2H), 7.51 (d, J 8.1 Hz, 1H), 7.71 (dd, J8.3, 2.5 Hz, 1H), 8.31 (d, J 2.3 Hz, 1H) 229 41-{[6-(benzylamino)pyridin-3- 324 (DMSO): 0.85 (t, J 7.1 Hz, 3H), 1.27(m, 4H), yl]methyl}-4-propylpyrrolidin-2-one 1.95 (dd, J 16.4, 7.6 Hz,1H), 2.23 (m, 1H), 2.39 (dd, J 16.2, 8.6 Hz, 1H), 2.82 (dd, J 9.3, 6.6Hz, 1H), 3.31 (m, 1H), 4.18 (m, 2H), 4.46 (d, J 6.1 Hz, 2H), 6.49 (d, J8.6 Hz, 1H), 7.05 (t, J 5.8 Hz, 1H), 7.28 (m, 5H), 7.84 (d, J 1.5 Hz,1H) 230 4 1-[(2-aminopyridin-3-yl)methyl]-4- 234 0.89 (t, J 7.2 Hz, 3H),1.32 (m, 4H), propylpyrrolidin-2-one 2.09 (m, 1H), 2.32 (m, 1H), 2.55(dd, J 16.7, 8.6 Hz, 1H), 2.89 (dd, J 9.5, 6.8 Hz, 1H), 3.36 (m, 1H),4.28 (m, 2H), 5.34 (s, 2H), 6.56 (dd, J 7.2, 5.1 Hz, 1H), 7.26 (m, 1H),8.02 (dd, J 5.0, 1.7 Hz, 1H) 231 4 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-0.84 (t, 7.20 Hz, 3H), 1.27 (m, 4H), 3-ylmethyl)pyrrolidin-2-one 2.09(dd, 16.42, 7.96 Hz, 1H), 2.24 (m, 1H), 2.55 (dd, 16.42, 8.59 Hz, 1H),2.86 (dd, 9.60, 6.57 Hz, 1H), 3.34 (m, 1H), 4.60 (m, 2H), 7.10 (dd,8.08, 4.67 Hz, 1H), 7.31 (s, 1H), 8.06 (d, 7.83 Hz, 1H), 8.34 (d, 4.29Hz, 1H), 10.51 (s, 1H) 232 4 1-[(2-isopropyl-1H-pyrrolo[2,3- 300 0.83(t, 7.18 Hz, 3H), 1.26 (m, 4H), b]pyridin-3-yl)methyl]-4- 1.48 (dd,7.05, 1.51 Hz, 6H), 2.08 (dd, 16.37, propylpyrrolidin-2-one 7.81 Hz,1H), 2.23 (m, 1H), 2.54 (dd, 16.37, 8.56 Hz, 1H), 2.82 (dd, 9.57, 6.80Hz, 1H), 3.28 (m, 1H), 3.44 (m, 1H), 4.62 (m, 2H), 7.10 (dd, 7.81, 4.91Hz, 1H), 8.02 (m, 1H), 8.29 (d, 4.28 Hz, 1H), 12.37 (s, 1H) 233 41-[(2-phenyl-1H-pyrrolo[2,3- 334 (DMSO) 0.87 (t, 6.95 Hz, 3H), 1.28 (m,4H), b]pyridin-3-yl)methyl]-4- 2.05 (dd, 16.42, 7.58 Hz, 1H), 2.23 (s,1H), propylpyrrolidin-2-one 2.52 (dd, 16.42, 8.59 Hz, 1H), 2.8 (d, 6.32Hz, 1H), 3.28 (m, 1H), 4.78 (s, 2H), 7.23 (dd, 7.83, 4.67 Hz, 1H), 7.59(d, 7.33 Hz, 1H), 7.66 (m, 2H), 7.79 (m, 2H), 8.08 (dd, 7.83, 1.26 Hz,1H), 8.38 (dd, 4.80, 1.52 Hz, 1H) 234 44-propyl-1-[(2-propyl-1H-pyrrolo[2,3- 300 0.83 (t, 6.95 Hz, 3H), 1.03(t, 7.33 Hz, 3H), b]pyridin-3-yl)methyl]pyrrolidin-2- 1.27 (m, 4H), 1.82(m, 2H), 2.08 (dd, 16.42, one 7.83 Hz, 1H), 2.23 (m, 1H), 2.54 (dd,16.42, 8.59 Hz, 1H), 2.84 (m, 3H), 3.30 (m, 1H), 4.59 (m, 2H), 7.09 (m,1H), 8.00 (d, 7.58 Hz, 1H), 8.20 (m, 1H), 11.41 (s, 1H) 235 41-[(6-bromo-1H-pyrrolo[2,3- 336/338 0.84 (t, 7.15 Hz, 3H), 1.13-1.46 (m,4H), b]pyridin-3-yl)methyl]-4- 2.09 (dd, 16.56, 7.78 Hz, 1H), 2.25 (m,1H), propylpyrrolidin-2-one 2.55 (dd, 16.56, 8.53 Hz, 1H), 2.86 (dd,9.54, 6.78 Hz, 1H), 3.34 (m, 1H), 4.58 (s, 2H), 7.24 (d, 8.28 Hz, 1H),7.36 (s, 1H), 7.96 (d, 8.28 Hz, 1H), 11.23 (s, 1H) 236 41-[(1-benzoyl-6-bromo-1H- 440/442 0.87 (t, 7.15 Hz, 3H), 1.20-1.40 (m,4H), pyrrolo[2,3-b]pyridin-3-yl)methyl]-4- 2.09 (dd, 16.56, 7.91 Hz,1H), 2.29 (m, 1H), propylpyrrolidin-2-one 2.56 (dd, 16.56, 8.66 Hz, 1H),2.89 (dd, 9.29, 6.78 Hz, 1H), 3.38 (m, 1H), 4.55 (m, 2H), 7.33 (d, 8.28Hz, 1H), 7.51 (t, 7.65 Hz, 2H), 7.65 (t, 7.53 Hz, 1H), 7.71 (s, 1H),7.78 (d, 7.53 Hz, 2H), 7.91 (d, 8.28 Hz, 1H) 237 41-[(6-phenyl-1H-pyrrolo[2,3- 334 0.83 (m, 3H), 1.27 (m, 4H), 2.10 (dd,16.56, b]pyridin-3-yl)methyl]-4- 8.03 Hz, 1H), 2.24 (m, 1H), 2.56 (dd,16.56, propylpyrrolidin-2-one 8.53 Hz, 1H), 2.85 (dd, 9.29, 7.03 Hz,1H), 3.33 (m, 1H), 4.59 (m, 2H), 7.08 (s, 1H), 7.46 (m, 1H), 7.52 (m,3H), 8.01 (d, 7.28 Hz, 2H), 8.12 (d, 8.03 Hz, 1H), 11.65 (s, 1H) 238 41-[(5-bromo-1H-pyrrolo[2,3- 356/358 2.25 (dd, 16.81, 8.28 Hz, 1H), 2.68(dd, b]pyridin-3-yl)methyl]-4-(2,2- 16.81, 8.78 Hz, 1H), 2.99 (dd, 9.29,7.15 Hz, difluorovinyl)pyrrolidin-2-one 1H), 3.10 (m, 1H), 3.45 (m, 1H),4.12 (ddd, 24.35, 9.54, 1.76 Hz, 1H), 4.58 (m, 2H), 7.33 (d, 2.26 Hz,1H), 8.17 (d, 2.01 Hz, 1H), 8.37 (d, 2.01 Hz, 1H), 10.32 (s, 1H) 239 41-[(7-oxido-1H-pyrrolo[2,3-b]pyridin- 274 0.84 (m, 3H), 1.27 (m, 4H),2.07 (dd, 16.56, 3-yl)methyl]-4-propylpyrrolidin-2-one 7.78 Hz, 1H),2.24 (m, 1H), 2.53 (dd, 16.56, 8.53 Hz, 1H), 2.84 (dd, 9.54, 6.78 Hz,1H), 3.32 (m, 1H), 4.55 (s, 2H), 7.07 (dd, 7.78, 6.40 Hz, 1H), 7.37 (s,1H), 7.86 (d, 7.78 Hz, 1H), 8.22 (d, 6.27 Hz, 1H), 13.35 (m, 1H) 240 44-propyl-1-(1H-pyrrolo[2,3-b]pyridin- 258 0.86 (t, J 7.15 Hz, 3H),1.20-1.42 (m, 4H), 4-ylmethyl)pyrrolidin-2-one 2.15 (dd, J 16.56, 7.78Hz, 1H), 2.31 (m, 1H), 2.61 (dd, J 16.56, 8.53 Hz, 1H), 2.86 (dd, J9.54, 6.90 Hz, 1H), 3.33 (t, J 8.0 Hz, 1H), 4.72 (d, J 15.0 Hz, 1H),4.76 (d, J 15.0 Hz, 1H), 6.59 (d, J 3.51 Hz, 1H), 6.97 (d, J 4.77 Hz,1H), 7.37 (d, J 3.51 Hz, 1H), 8.34 (s, 1H), 10.79 (s (broad), 1H) 241 44-propyl-1-(1H-pyrrolo[2,3-b]pyridin- 258 (DMSO): 0.82 (t, J 7.15 Hz,3H), 5-ylmethyl)pyrrolidin-2-one 1.18-1.35 (m, 4H), 1.98 (dd, J 16.31,7.78 Hz, 1H), 2.24 (m, 1H), 2.42 (dd, J 16.31, 8.78 Hz, 1H), 2.85 (dd, J9.29, 6.90 Hz, 1H), 3.35 (m, 1H, overlapped with solvent signal), 4.44(m, 2H), 6.42 (d, J 1.25 Hz, 1H), 7.47 (t, J 2.76 Hz, 1H), 7.80 (d, J0.50 Hz, 1H), 8.11 (d, J 1.25 Hz, 1H), 11.63 (s, 1H) 242 44-propyl-1-(1H-pyrrolo[2,3-c]pyridin- 258 0.84 (t, 7.05 Hz, 3H), 1.28(m, 4H), 2-ylmethyl)pyrrolidin-2-one 2.10 (dd, 16.62, 8.06 Hz, 1H), 2.26(m, 1H), 2.56 (dd, 16.62, 8.56 Hz, 1H), 2.88 (dd, 9.57, 6.80 Hz, 1H),3.37 (m, 1H), 4.63 (m, 2H), 7.40 (s, 1H), 7.63 (dd, 5.54, 1.01 Hz, 1H),8.25 (d, 5.54 Hz, 1H), 8.83 (s, 1H), 1087 (s, 1H) 243 44-propyl-1-(1H-pyrrolo[2,3-c]pyridin- 258 0.78 (t, 7.03 Hz, 3H), 1.20(m, 4H), 3-ylmethyl)pyrrolidin-2-one 1.94 (dd, 16.31, 7.53 Hz, 1H), 2.17(m, 1H), 2.39 (dd, 16.56, 8.66 Hz, 1H), 2.77 (dd, 9.54, 6.53 Hz, 1H),4.48 (m, 2H), 7.49 (d, 5.27 Hz, 1H), 7.55 (s, 1H), 8.07 (d, 5.52 Hz,1H), 8.72 (s, 1H), 11.63 (m, 1H) 244 44-propyl-1-(1H-pyrrolo[3,2-b]pyridin- 258 0.85 (t, 7.07 Hz, 3H), 1.26(m, 4H), 2.07 (m, 3-ylmethyl)pyrrolidin-2-one 1H), 2.26 (m, 1H), 2.51(dd, 16.67, 8.72 Hz, 1H), 3.12 (dd, 10.11, 6.69 Hz, 1H), 3.62 (dd, 9.85,8.08 Hz, 1H), 4.72 (m, 2H), 7.13 (dd, 8.08, 4.55 Hz, 1H), 7.44 (s, 1H),7.68 (dd, 8.08, 1.14 Hz, 1H), 8.48 (d, 1.01 Hz, 1H), 8.94 (s, 1H) 245 44-propyl-1-(1H-pyrrolo[3,2-c]pyridin- 258 0.84 (t, 7.18 Hz, 3H), 1.29(m, 4H), 2-ylmethyl)pyrrolidin-2-one 2.10 (dd, 16.62, 7.93 Hz, 1H), 2.27(m, 1H), 2.56 (dd, 16.62, 8.56 Hz, 1H), 2.92 (dd, 9.32, 6.92 Hz, 1H),3.40 (m, 1H), 4.67 (m, 2H), 7.25 (s, 1H), 7.33 (d, 5.79 Hz, 1H), 8.31(d, 5.79 Hz, 1H), 9.00 (s, 1H), 10.34 (s, 1H) 246 44-propyl-1-(1H-pyrrolo[3,2-c]pyridin- 258 (DMSO) 0.79 (m, 3H), 1.21 (m,4H), 3-ylmethyl)pyrrolidin-2-one 1.96 (dd, 16.17, 7.58 Hz, 1H), 2.19 (m,1H), 2.41 (dd, 16.42, 8.59 Hz, 1H), 2.81 (m, 1H), 3.32 (t, 8.72 Hz, 1H),4.53 (m, 2H), 7.38 (d, 5.56 Hz, 1H), 7.43 (s, 1H), 8.17 (d, 5.56 Hz,1H), 8.82 (s, 1H), 11.49 (s, 1H) 247 4 4-propyl-1-(1,3,4-thiadiazol-2-226 0.90 (t, J 7.28 Hz, 3H), 1.25-1.35 (m, 2H),ylmethyl)pyrrolidin-2-one 1.37-1.45 (m, 2H), 2.10 (dd, J 16.81, 7.78 Hz,1H), 2.37 (m, 1H), 2.56 (dd, J 16.81, 8.53 Hz, 1H), 3.08 (dd, J 9.54,6.78 Hz, 1H), 3.56 (dd, J 9.54, 7.91 Hz, 1H), 4.92 (s, 2H), 9.12 (s, 1H)248 1-[(2-amino-1,3-thiazol-5- 198 1.89 (m, 2H), 2.18 (t, J 8.3 Hz, 2H),yl)methyl]pyrrolidin-2-one 3.15-3.27 (m, 2H with solvent peak), 4.30 (s,2H), 6.74 (s (broad), 2H), 6.76 (s, 1H) 2491-(1,3-thiazol-5-ylmethyl)pyrrolidin- (182) 1.91 (m, 2H), 2.21 (t, J7.63 Hz, 2H), 3.24 (t, 2-one J 6.9 Hz, 2H), 4.61 (s, 2H), 7.82 (d, J 0.7Hz, 1H), 9.04 (d, J 0.7 Hz, 1H) 250 41-[(2-chloro-1,3-thiazol-5-yl)methyl]- 347 2.57 (dd, J 16.87, 7.93 Hz,1H), 2.86 (dd, J 4-(2,3,5-trifluorophenyl)pyrrolidin-2- 16.87, 8.94 Hz,1H), 3.35 (dd, J 9.06, 6.55 Hz, one 1H), 3.81 (m, 2H), 4.63 (m, 2H),6.68 (m, 1H), 6.86 (m, 1H), 7.43 (s, 1H) 251 41-{[2-(dimethylamino)-1,3-thiazol-5- 356 2.53 (dd, J 16.87, 7.30 Hz,1H), 2.86 (dd, J yl]methyl}-4-(2,3,5- 16.87, 9.06 Hz, 1H), 3.08 (s, 6H),3.32 (dd, trifluorophenyl)pyrrolidin-2-one J 9.57, 6.04 Hz, 1H), 3.72(t, J 9.2 Hz, 1H), 3.81 (m, 1H), 4.44 (d, J 15.3 Hz, 1H), 4.44 (d, J15.3 Hz, 1H), 6.65-6.70 (m, 1H), 6.80-6.85 (m, 1H), 7.02 (s, 1H) 252 41-{[2-(methylamino)-1,3-thiazol-5- 342 2.54 (dd, J 16.87, 7.43 Hz, 1H),2.86 (dd, J yl]methyl}-4-(2,3,5- 17.12, 8.94 Hz, 1H), 2.96 (s, 3H), 3.33(dd, trifluorophenyl)pyrrolidin-2-one J 9.57, 6.29 Hz, 1H), 3.73 (t, J8.81 Hz, 1H), 3.78-3.85 (m, 1H), 4.46 (d, J 15.3 Hz, 1H), 4.58 (d, J15.3 Hz, 1H), 5.15 (s (broad), 1H), 6.65-6.70 (m, 1H), 6.80-6.85 (m,1H), 6.99 (s, 1H) 253 4 1-[(2-pyrrolidin-1-yl-1,3-thiazol-5- 382 2.0-2.1(m, 4H), 2.53 (dd, J 16.87, 7.30 Hz, yl)methyl]-4-(2,3,5- 1H), 2.86 (dd,J 16.87, 8.94 Hz, 1H), trifluorophenyl)pyrrolidin-2-one 3.32 (dd, J9.57, 6.17 Hz, 1H), 3.40-3.50 (m, 4H), 3.72 (t, J 9.3 Hz, 1H), 3.80 (m,1H), 4.47 (d, J 15.3 Hz, 1H), 4.60 (d, J 15.3 Hz, 1H), 6.65-6.70 (m,1H), 6.80-6.85 (m, 1H), 7.03 (s, 1H) 254 4 5-{[2-oxo-4-(2,3,5- 329 2.56(dd, J 16.87, 7.68 Hz, 1H), 2.84 (dd, J trifluorophenyl)pyrrolidin-1-16.87, 8.94 Hz, 1H), 3.37 (t, J 6.3 Hz, 1H),yl]methyl}-1,3-thiazol-2(3H)-one 3.73-3.89 (m, 2H), 4.35 (s~2d, 2H),6.54 (s, 1H), 6.70-6.75 (m, 1H), 6.82-6.87 (m, 1H), 8.13 (s (broad), 1H)255 4 4-phenyl-1-{[3- 362 2.70 (dd, J 17.32, 8.66 Hz, 1H), 2.93 (dd, J(trifluoromethyl)[1,2,4]triazolo[4,3- 17.07, 8.78 Hz, 1H), 3.41 (dd, J9.03, 7.28 Hz, b]pyridazin-7-yl]methyl}pyrrolidin-2- 1H), 3.67 (m, 1H),3.78 (t, J 9.00 Hz, 1H), one 4.57 (d, J 15.80 Hz, 1H), 4.72 (d, J 15.80Hz, 1H), 7.20 (d, J 7.30 Hz, 2H), 7.25-7.29 (m, 1H), 7.34 (t, J 7.03 Hz,2H) 8.04 (s, 1H), 8.56 (d, J 1.76 Hz, 1H) 256 4 4-phenyl-1-[(3- 370(DMSO): 2.60 (dd, J 16.31, 9.29 Hz, 1H),phenyl[1,2,4]triazolo[4,3-b]pyridazin- 2.77 (dd, J 16.56, 8.66 Hz, 1H),3.39 (t, J 7-yl)methyl]pyrrolidin-2-one 8.28 Hz, 1H), 3.74 (q, J 8.53Hz, 1H), 3.79 (t, J 8.53 Hz, 1H), 4.56 (d, J 16.06 Hz, 1H), 4.67 (d, J16.06 Hz, 1H), 7.21-7.27 (m, 1H), 7.30-7.35 (m, 4H), 7.55-7.65 (m, 3H),8.28 (s, 1H), 8.37 (d, J 7.03 Hz, 2H), 8.65 (d, J 2.01 Hz, 1H) 257 44-phenyl-1-{[3- 362 2.67 (dd, J 17.07, 8.53 Hz, 1H), 2.88 (dd, J(trifluoromethyl)[1,2,4]triazolo[4,3- 17.07, 8.53 Hz, 1H), 3.61-3.73 (m,2H), b]pyridazin-8-yl]methyl}pyrrolidin-2- 4.05 (t, J 8.03 Hz, 1H), 4.96(d, J 16.3 Hz, one 1H), 5.02 (d, J 16.3 Hz, 1H), 7.25-7.30 (m, 4H), 7.34(t, J 7.8 Hz, 2H), 8.50 (d, J 4.52 Hz, 1H) 258 4 4-propyl-1-{[3- 3280.92 (t, J 7.28 Hz, 3H), 1.26-1.34 (m, 2H),(trifluoromethyl)[1,2,4]triazolo[4,3- 1.39-1.50 (m, 2H), 2.14 (dd, J16.56, 8.03 Hz, b]pyridazin-8-yl]methyl}pyrrolidin-2- 1H), 2.45 (m, 1H),2.58 (m, 1H), one 3.25 (dd, J 9.29, 7.28 Hz, 1H), 3.73 (t, J 8.78 Hz,1H), 4.87 (d, J 16.5 Hz, 1H), 4.97 (d, J 16.5 Hz, 1H), 7.21 (d, J 4.27Hz, 1H), 8.52 (d, J 4.27 Hz, 1H) 259 4 4-phenyl-1-[(3- 370 (DMSO): 2.61(dd, J 16.31, 9.54 Hz, 1H), phenyl[1,2,4]triazolo[4,3-b]pyridazin- 2.79(dd, J 16.56, 8.78 Hz, 1H), 3.52 (t, J 8-yl)methyl]pyrrolidin-2-one 8.53Hz, 1H), 3.74 (quint, J 8.63 Hz, 1H), 3.90 (t, J 8.78 Hz, 1H), 4.87 (d,J 17.07 Hz, 1H), 4.97 (d, J 17.07 Hz, 1H), 7.24-7.27 (m, 2H), 7.32-7.37(m, 4H), 7.56-7.65 (m, 3H), 8.38 (d, J 7.03 Hz, 2H), 8.70 (d, J 4.52 Hz,1H) 260 4 1-[(6-chloro-3- 370/372 0.89 (t, J 7.28 Hz, 3H), 1.26-1.34 (m,2H), phenyl[1,2,4]triazolo[4,3-b]pyridazin- 1.39-1.45 (m, 2H), 2.10 (dd,J 7.02, 15.06 Hz, 8-yl)methyl]-4-propylpyrrolidin-2-one 1H), 2.38-2.50(m, 2H overlapped with solvent signal), 3.15 (dd, J 9.03, 7.15 Hz, 1H),3.60 (t, J 8.78 Hz, 1H), 4.78 (d, J 17.3 Hz, 1H), 4.89 (d, J 17.3 Hz,1H), 7.29 (s, 1H), 7.57-7.67 (m, 3H), 8.30 (d, J 8.28 Hz, 2H) 261 41-[(6-chloro[1,2,4]triazolo[4,3- 328/330 2.59 (dd, J 16.31, 9.29 Hz,1H), 2.78 (dd, J b]pyridazin-8-yl)methyl]-4- 16.31, 8.78 Hz, 1H), 3.49(t, J 8.28 Hz, 1H), phenylpyrrolidin-2-one 3.74 (quint, J 8.53 Hz, 1H),3.87 (t, J 8.66 Hz, 1H), 4.82 (d, J 17.57 Hz, 1H), 4.92 (d, J 17.57 Hz,1H), 7.23-7.36 (m, 6H), 9.70 (s, 1H) 262 4 1-{[6-chloro-3- 396/398 2.59(dd, J 16.31, 9.41 Hz, 1H), 2.78 (dd, J(trifluoromethyl)[1,2,4]triazolo[4,3- 16.31, 8.78 Hz, 1H), 3.48 (m, 1H),b]pyridazin-8-yl]methyl}-4- 3.73 (quint, J 8.53 Hz, 1H), 3.85 (t, J 8.66Hz, 1H), phenylpyrrolidin-2-one 4.87 (d, J 17.5 Hz, 1H), 4.93 (d, J 17.5Hz, 1H), 7.25 (m, 1H), 7.34-7.36 (m, 4H), 7.58 (s, 1H) 263 41-[(6-chloro-3- 404/406 (DMSO): 2.61 (dd, J 16.56, 9.29 Hz, 1H),phenyl[1,2,4]triazolo[4,3-b]pyridazin- 2.79 (dd, J 16.31, 8.66 Hz, 1H),3.51 (t, J 8-yl)methyl]-4-phenylpyrrolidin-2- 8.54 Hz, 1H), 3.76 (quint,J 8.50 Hz, 1H), one 3.90 (t, J 8.66 Hz, 1H), 4.87 (d, J 17.57 Hz, 1H),4.97 (d, J 17.57 Hz, 1H), 7.23-7.28 (m, 1H), 7.31-7.37 (m, 5H),7.58-7.66 (m, 3H), 8.30 (d, J 7.03 Hz, 2H) 264 41-[(2-fluoroindolizin-3-yl)methyl]-4- 275 0.78 (t, J 7.15 Hz, 3H),1.10-1.27 (m, 4H), propylpyrrolidin-2-one 1.97 (dd, J 16.31, 7.53 Hz,1H), 2.21 (m, 1H), 2.42 (dd, J 16.31, 8.66 Hz, 1H), 2.78 (dd, J 9.29,6.53 Hz, 1H), 3.28 (dd, J 9.29, 8.28 Hz, 1H), 4.67 (s, 2H), 6.32 (s,1H), 6.71 (t, J 7.03 Hz, 1H overlapped with solvent signal), 6.85 (t, J8.78 Hz, 1H), 7.42 (d, J 9.03 Hz, 1H), 8.13 (d, J 7.03 Hz, 1H) 265 41-(1H-1,2,3-benzotriazol-1- 259 0.84 (t, 7.07 Hz, 3H), 1.27 (m, 4H),ylmethyl)-4-propylpyrrolidin-2-one 2.07 (dd, 16.92, 8.08 Hz, 1H), 2.29(m, 1H), 2.54 (dd, 16.92, 8.59 Hz, 1H), 3.01 (dd, 9.85, 6.95 Hz, 1H),3.55 (dd, 9.60, 7.83 Hz, 1H), 6.09 (s, 2H), 7.40 (m, 1H), 7.52 (m, 1H),7.85 (d, 8.34 Hz, 1H), 8.06 (d, 8.34 Hz, 1H) 266 41-[(6-bromo-2-chloro-1H- 371/373 0.89 (t, 7.15 Hz, 3H), 1.33 (m, 4H),imidazo[4,5-b]pyridin-1-yl)methyl]-4- 2.10 (dd, 17.06, 8.16 Hz, 1H),2.32 (m, 1H), propylpyrrolidin-2-one 2.54 (m, 1H), 3.04 (m, 1H), 3.54(m, 1H), 5.65 (s, 2H), 8.24 (d, 1.65 Hz, 1H), 8.59 (d, 1.47 Hz, 1H) 2674 1-[(6-bromo-2-phenyl-1H- 413/415 (DMSO) 0.81 (t, 6.90 Hz, 3H), 1.18(m, 4H), imidazo[4,5-b]pyridin-1-yl)methyl]-4- 1.92 (s, 1H), 2.00 (dd,17.07, 8.03 Hz, 1H), propylpyrrolidin-2-one 2.16 (m, 1H), 2.48 (m, 1H),2.96 (m, 1H), 5.73 (m, 2H), 7.58 (m, 3H), 7.72 (m, 2H), 8.18 (d, 1.76Hz, 1H), 8.63 (d, 1.51 Hz, 1H) 268 4 1-(3H-imidazo[4,5-b]pyridin-3- 2590.87 (t, 7.04 Hz, 3H), 1.30 (m, 4H), ylmethyl)-4-propylpyrrolidin-2-one2.06 (dd, 16.85, 8.05 Hz, 1H), 2.32 (m, 1H), 2.52 (dd, 16.85, 8.55 Hz,1H), 3.15 (dd, 9.56, 7.04 Hz, 1H), 3.68 (dd, 9.31, 8.05 Hz, 1H), 5.73(s, 2H), 7.29 (m, 1H), 8.09 (dd, 8.05, 1.26 Hz, 1H), 8.30 (s, 1H), 8.41(dd, 4.78, 1.26 Hz, 1H) 269 4 1-[(6-bromo-3H-imidazo[4,5- 337/339 0.88(m, 3H), 1.31 (m, 4H), 2.05 (dd, 17.06, b]pyridin-3-yl)methyl]-4- 8.07Hz, 1H), 2.33 (m, 1H), 2.52 (dd, 17.06, propylpyrrolidin-2-one 8.53 Hz,1H), 3.13 (m, 1H), 3.66 (m, 1H), 5.68 (s, 2H), 8.22 (s, 1H), 8.28 (s,1H), 8.46 (s, 1H) 270 4 1-[(6-bromo-2-chloro-3H- 371/373 0.87 (m, 3H),1.31 (m, 4H), 2.10 (m, 1H), imidazo[4,5-b]pyridin-3-yl)methyl]-4- 2.32(m, 1H), 2.53 (m, 1H), 2.97 (dd, 9.54, propylpyrrolidin-2-one 6.97 Hz,1H), 3.49 (m, 1H), 5.77 (m, 2H), 8.11 (d, 2.02 Hz, 1H), 8.44 (d, 1.83Hz, 1H) 271 4 1-[(6-bromo-2-phenyl-3H- 413/415 (DMSO) 0.84 (m, 3H), 1.23(m, 4H), imidazo[4,5-b]pyridin-3-yl)methyl]-4- 1.82 (m, 1H), 2.08 (m,1H), 2.25 (dd, 16.56, 8.53 Hz, propylpyrrolidin-2-one 1H), 2.98 (m, 1H),3.36 (m, 1H), 5.8 (m, 2H), 7.57 (m, 3H), 7.83 (m, 2H), 8.44 (d, 2.01 Hz,1H), 8.52 (d, 2.01 Hz, 1H) 272 4 1-[(6-bromo-2-cyclopropyl-3H- 397/3991.22 (m, 4H), 2.24 (dd, 17.06, 8.34 Hz, 1H),imidazo[4,5-b]pyridin-3-yl)methyl]-4- 2.49 (m, 1H), 2.66 (dd, 17.06,8.25 Hz, 1H), (2,2-difluorovinyl)pyrrolidin-2-one 3.14 (m, 2H), 3.65 (m,1H), 4.16 (m, 1H), 5.83 (m, 2H), 8.00 (d, 1.65 Hz, 1H), 8.30 (d, 1.65Hz, 1H) 273 4 1-[(3-chloro-7H-imidazo[4,5- 294/296 0.89 (t, 7.20 Hz,3H), 1.32 (m, 4H), c]pyridazin-7-yl)methyl]-4- 2.06 (dd, 17.10, 8.30 Hz,1H), 2.36 (m, 1H), propylpyrrolidin-2-one 2.52 (m, 1H), 3.27 (dd, 9.56,7.29 Hz, 1H), 3.82 (dd, 9.56, 8.05 Hz, 1H), 5.82 (m, 2H), 7.88 (s, 1H),8.54 (s, 1H) 274 4 1-[(2-chloro-1H-indol-1-yl)methyl]-4- 291/293 0.84(t, 7.06 Hz, 3H), 1.26 (m, $$H), 2.06 (dd, propylpyrrolidin-2-one 16.87,7.98 Hz, 1H), 2.24 (m, 1H), 2.51 (dd, 16.87, 8.53 Hz, 1H), 2.85 (dd,9.54, 6.97 Hz, 1H), 3.38 (m, 1H), 5.68 (dd, 16, 20 Hz, 2H), 6.48 (s,1H), 7.15 (m, 1H), 7.23 (m, 1H), 7.51 (d, 7.70 Hz, 1H), 7.60 (d, 8.25Hz, 1H) 275 4 1-[(5-methyl-1H-indol-1-yl)methyl]-4- 271 0.83 (t, 7.06Hz, 3H), 1.25 (m, 4H), propylpyrrolidin-2-one 2.05 (dd, 16.69, 8.16 Hz,1H), 2.23 (m, 1H), 2.49 (s, 3H), 2.50 (dd, 8, 16 Hz, 1H), 2.81 (dd,9.17, 6.88 Hz, 1H), 3.31 (m, 1H), 5.54 (s, 2H), 6.43 (d, 2.93 Hz, 1H),7.05 (d, 8 Hz, 1H), 7.11 (d, 3.12 Hz, 1H), 7.40 (m, 2H) 276 41-[(6-methyl-1H-indol-1-yl)methyl]-4- 271 0.84 (t, 7.06 Hz, 3H), 1.26(m, 4H), propylpyrrolidin-2-one 2.06 (dd, 16.69, 8.07 Hz, 1H), 2.25 (m,1H), 2.51 (m, 4H), 2.83 (dd, 9.35, 6.97 Hz, 1H), 3.33 (m, 1H), 5.53 (d,2.38 Hz, 2H), 6.46 (d, 3.12 Hz, 1H), 6.97 (d, 7.89 Hz, 1H), 7.08 (d,3.30 Hz, 1H), 7.31 (s, 1H), 7.49 (d, 8.07 Hz, 1H) 277 41-[(2-phenyl-1H-indol-1-yl)methyl]-4- 333 0.76 (m, 3H), 1.10 (m, 4H),1.90 (m, 1H), propylpyrrolidin-2-one 2.07 (m, 1H), 2.36 (m, 2H), 2.82(m, 1H), 5.68 (m, 2H), 6.55 (s, 1H), 7.17 (m, 1H), 7.26 (m, 1H), 7.46(m, 5H), 7.61 (m, 2H) 278 4 1-[(5-fluoro-1H-indol-1-yl)methyl]-4- 2750.84 (m, 3H), 1.25 (m, 4H), 2.06 (dd, 16.87, propylpyrrolidin-2-one 7.89Hz, 1H), 2.24 (m, 1H), 2.52 (dd, 16.87, 8.53 Hz, 1H), 2.81 (dd, 9.17,6.88 Hz, 1H), 3.32 (m, 1H), 5.54 (s, 2H), 6.46 (d, 3.12 Hz, 1H), 6.97(td, 8.99, 2.43 Hz, 1H), 7.19 (d, 3.12 Hz, 1H), 7.25 (m, 1H), 7.45 (d,4.22 Hz, 1H) 279 4 1-[(5-bromo-1H-indol-1-yl)methyl]-4- 335/337 0.84 (t,7.06 Hz, 3H), 1.26 (m, 4H), propylpyrrolidin-2-one 2.05 (dd, 16.87, 7.89Hz, 1H), 2.25 (m, 1H), 2.52 (dd, 16.87, 8.62 Hz, 1H), 2.81 (dd, 9.17,6.88 Hz, 1H), 3.32 (m, 1H), 5.54 (d, 1.47 Hz, 2H), 6.45 (m, 1H), 7.16(d, 3.30 Hz, 1H), 7.30 (dd, 8.80, 1.83 Hz, 1H), 7.42 (m, 1H), 7.74 (d,1.65 Hz, 1H) 280 4 1-[(5-chloro-1H-indol-1-yl)methyl]-4- 291/293 0.84(t, 7.06 Hz, 3H), 1.25 (m, 4H), propylpyrrolidin-2-one 2.05 (dd, 16.87,7.98 Hz, 1H), 2.25 (m, 1H), 2.52 (dd, 16.87, 8.62 Hz, 1H), 2.81 (dd,9.17, 6.88 Hz, 1H), 3.32 (m, 1H), 5.54 (d, 1.65 Hz, 2H), 6.45 (m, 1H),7.17 (m, 2H), 7.46 (d, 8.80 Hz, 1H), 7.57 (d, 1.83 Hz, 1H) 281 41-(2,3-dihydro-1H-indol-1-ylmethyl)- 259 0.89 (t, 7.15 Hz, 3H), 1.32 (m,4H), 4-propylpyrrolidin-2-one 2.08 (dd, 16.69, 7.89 Hz, 1H), 2.30 (m,1H), 2.52 (dd, 16.69, 8.62 Hz, 1H), 3.00 (m, 3H), 3.47 (m, 3H), 4.70 (s,2H), 6.65 (m, 2H), 7.06 (m, 2H) 282 4 1-[(5-fluoro-2-phenyl-1H-indol-1-351 0.77 (m, 3H), 1.10 (m, 4H), 1.93 (m, 1H),yl)methyl]-4-propylpyrrolidin-2-one 2.06 (d, 7.52 Hz, 1H), 2.30 (dd,9.35, 6.69 Hz, 1H), 2.40 (dd, 16.51, 8.34 Hz, 1H), 2.80 (dd, 9.35, 7.98Hz, 1H), 5.65 (m, 2H), 6.49 (s, 1H), 6.97 (td, 9.17, 2.43 Hz, 1H), 7.25(m, 2H), 7.50 (m, 6H) 322 4 1-[(2-oxo-4-propylpyrrolidin-1- 282 (DMSO):0.78 (t, J 7.15 Hz, 3H), yl)methyl]-1H-indole-2-carbonitrile 1.11-1.27(m, 4H), 1.98 (dd, J 16.56, 7.53 Hz, 1H), 2.23 (m, 1H), 2.43 (dd, J16.56, 8.53 Hz, 1H), 2.87 (dd, J 6.77, 9.28 Hz, 1H), 3.41 (t, J 8.78 Hz,1H), 5.69 (d, J 14.8 Hz, 1H), 5.69 (d, J 14.8 Hz, 1H), 7.23 (t, J 7.53Hz, 1H), 7.43 (t, J 7.03 Hz, 1H), 7.52 (s, 1H), 7.72 (dd, J 6.5, 8.2 Hz,2H) 323 4 1-[(2-bromo-1H-indol-1-yl)methyl]-4- 335/337 (DMSO): 0.76 (t,J 7.15 Hz, 3H), propylpyrrolidin-2-one 1.05-1.25 (m, 4H), 1.96 (dd, J6.56, 7.53 Hz, 1H), 2.18 (m, 1H), 2.41 (dd, J 16.56, 8.66 Hz, 1H), 2.78(dd, J 9.29, 6.53 Hz, 1H), 3.33 (m, 1H overlapped with solvent signal),5.64 (s, 2H), 6.72 (s, 1H), 7.09 (t, J 7.28 Hz, 1H), 7.17 (t, J 7.03 Hz,1H), 7.51 (d, J 7.78 Hz, 1H), 7.62 (d, J 8.03 Hz, 1H). 324 41-[(2,5-dichloro-1H-indol-1- 325/327 (DMSO): 0.78 (t, J 7.03 Hz, 3H),yl)methyl]-4-propylpyrrolidin-2-one 1.11-1.25 (m, 4H), 1.96 (dd, J16.56, 7.53 Hz, 1H), 2.20 (m, 1H), 2.41 (dd, J 16.81, 8.53 Hz, 1H), 2.81(dd, J 9.29, 6.53 Hz, 1H), 3.36 (t, J 9.04 Hz, 1H partially overlappedwith solvent signal), 5.63 (s, 2H), 6.64 (s, 1H), 7.23 (dd, J 8.78, 2.26Hz, 1H), 7.58 (d, J 2.01 Hz, 1H), 7.64 (d, J 8.78 Hz, 1H) 283 41-[(6-amino-9H-purin-9-yl)methyl]-4- 275 0.88 (t, 7.18 Hz, 3H), 1.30 (m,4H), propylpyrrolidin-2-one 2.06 (dd, 16.87, 8.06 Hz, 1H), 2.34 (m, 1H),2.52 (dd, 16.87, 8.69 Hz, 1H), 3.15 (dd, 9.57, 7.05 Hz, 1H), 3.67 (dd,9.57, 8.06 Hz, 1H), 5.61 (s Hz, 2H), 5.81 (s, 2H), 8.05 (s, 1H), 8.38(s, 1H) 284 4 4-propyl-1-(9H-purin-9- 260 0.88 (t, 7.07 Hz, 3H), 1.32(m, 4H), ylmethyl)pyrrolidin-2-one 2.06 (dd, 16.92, 8.08 Hz, 1H), 2.35(m, 1H), 2.53 (dd, 17.18, 8.59 Hz, 1H), 3.17 (dd, 9.60, 7.07 Hz, 1H),3.70 (m, 1H), 5.70 (s, 2H), 8.34 (s, 1H), 9.01 (s, 1H), 9.17 (s, 1H) 2854 1-{[6-(cyclopropylamino)-9H-purin-9- 315 (DMSO) 0.61 (m, 2H), 0.72 (m,2H), 0.84 (t, yl]methyl}-4-propylpyrrolidin-2-one 7.16 Hz, 3H), 1.24 (m,4H), 1.96 (dd, 16.58, 7.66 Hz, 1H), 2.24 (m, 1H), 2.39 (m, 1H), 3.07(dd, 9.29, 6.78 Hz, 1H), 3.59 (m, 1H), 5.54 (t, 4.52 Hz, 2H), 7.93 (s,NH, 1H), 8.06 (s, 1H), 8.28 (s, 1H) 286 41-{[6-(benzylamino)-9H-purin-9- 365 (DMSO) 0.81 (t, 7.16 Hz, 3H), 1.23(m, 4H), yl]methyl}-4-propylpyrrolidin-2-one 1.95 (dd, 16.58, 7.66 Hz,1H), 2.24 (m, 1H), 2.39 (m, 1H), 3.08 (dd, 9.29, 7.03 Hz, 1H), 3.59 (m,1H), 4.71 (s, 2H), 5.54 (m, 2H), 7.28 (m, 5H), 8.09 (s, 1H), 8.24 (s,1H), 8.32 (s, NH, 1H) 287 4 4-propyl-1-{[6-(propylamino)-9H- 317 (DMSO)0.81 (t, 7.03 Hz, 5H), 0.89 (t, 7.41 Hz,purin-9-yl]methyl}pyrrolidin-2-one 5H), 1.24 (m, 7H), 1.60 (m, 3H), 1.96(dd, 16.58, 7.79 Hz, 2H), 2.24 (m, 2H), 2.39 (m, 2H), 3.07 (dd, 9.04,6.91 Hz, 2H), 3.43 (m, 2H), 3.59 (m, 1H), 5.53 (m, 2H), 7.82 (s, NH,1H), 8.05 (s, 1H), 8.24 (s, 1H) 288 4 1-({6-[(cyclopropylmethyl)amino]-329 (DMSO) 0.27 (d, 4.52 Hz, 2H), 0.41 (m, 2H), 9H-purin-9-yl}methyl)-4-0.81 (m, 3H), 1.21 (m, 4H), 1.96 (dd, propylpyrrolidin-2-one 16.58, 7.79Hz, 1H), 2.24 (m, 1H), 2.39 (m, 1H), 3.07 (m, 1H), 3.4 (m, 2H), 3.59 (m,1H), 5.53 (m, 2H), 7.87 (s, NH, 1H), 8.06 (s, 1H), 8.23 (s, 1H) 289 44-propyl-1-[(6-pyrrolidin-1-yl-9H- 329 (DMSO) 0.82 (t, 7.16 Hz, 3H),1.24 (m, 4H), purin-9-yl)methyl]pyrrolidin-2-one 1.95 (m, 5H), 2.23 (m,1H), 2.39 (dd, 16.58, 8.54 Hz, 1H), 3.57 (m, 3H), 4.04 (m, 2H), 5.54 (m,2H), 8.04 (s, 1H), 8.24 (s, 1H) 290 4 1-[(5-bromo-3-phenyl-1H- 413/4151.47 (t, 7.15 Hz, 3H), 1.91 (m, 4H),pyrazolo[3,4-b]pyridin-1-yl)methyl]- 2.57 (dd, 16.56, 8.28 Hz, 1H), 2.90(m, 1H), 4-propylpyrrolidin-2-one 3.02 (m, 1H), 3.86 (dd, 9.79, 7.40 Hz,1H), 4.38 (dd, 9.54, 7.91 Hz, 1H), 6.44 (s, 2H), 8.16 (m, 5H), 8.67 (d,2.26 Hz, 1H), 9.30 (d, 2.26 Hz, 1H) 291 4 1-[(5-bromo-2H-pyrazolo[3,4-337/339 0.88 (t, 7.05 Hz, 3H), 1.32 (m, 4H), 2.07 (m,b]pyridin-2-yl)methyl]-4- 1H), 2.35 (m, 1H), 2.52 (dd, 16.87, 8.56 Hz,propylpyrrolidin-2-one 1H), 3.24 (dd, 9.57, 7.30 Hz, 1H), 3.77 (m, 1H),5.80 (m, 2H), 8.08 (m, 1H), 8.18 (m, 1H), 8.70 (m, 1H) 292 41-[(5-bromo-3-phenyl-2H- 413/415 0.86 (t, 7.15 Hz, 3H), 1.30 (m, 4H),2.08 (m, pyrazolo[3,4-b]pyridin-2-yl)methyl]- 1H), 2.30 (m, 1H), 2.55(dd, 16.81, 8.53 Hz, 4-propylpyrrolidin-2-one 1H), 3.05 (dd, 9.54, 6.78Hz, 1H), 3.57 (m, 1H), 6.00 (m, 2H), 7.48 (m, 3H), 7.92 (d, 7.53 Hz,2H), 8.46 (d, 2.01 Hz, 1H), 8.62 (d, 2.01 Hz, 1H) 293 41-[(2-chloro-1H-pyrrolo[2,3- 292/294 0.84 (m, 3H), 1.26 (m, 4H), 2.08(dd, 16.81, b]pyridin-1-yl)methyl]-4- 7.91 Hz, 1H), 2.24 (m, 1H), 2.53(dd, 16.56, propylpyrrolidin-2-one 8.53 Hz, 1H), 2.82 (dd, 9.79, 6.78Hz, 1H), 3.33 (m, 1H), 5.88 (m, 2H), 6.46 (s, 1H), 7.11 (dd, 7.78, 4.77Hz, 1H), 7.82 (d, 7.78 Hz, 1H), 8.30 (d, 4.77 Hz, 1H) 294 44-propyl-1-(1H-pyrrolo[3,2-b]pyridin- 258 (DMSO) 0.78 (t, 7.03 Hz, 3H),1.18 (m, 4H), 1-ylmethyl)pyrrolidin-2-one 1.96 (dd, 16.56, 7.53 Hz, 1H),2.20 (m, 1H), 2.41 (dd, 16.81, 8.53 Hz, 1H), 2.83 (dd, 9.29, 6.53 Hz,1H), 3.39 (m, 1H), 5.61 (m, 2H), 6.59 (d, 3.01 Hz, 1H), 7.16 (dd, 8.28,4.52 Hz, 1H), 7.73 (d, 3.26 Hz, 1H), 7.95 (d, 8.28 Hz, 1H), 8.36 (dd,4.52, 1.13 Hz, 1H) 295 4 1-(3,4-dihydroquinolin-1(2H)- 273 0.88 (t, 7.15Hz, 3H), 1.22-1.44 (m, 4H), ylmethyl)-4-propylpyrrolidin-2-one 1.94 (m,2H), 2.07 (dd, 16.56, 7.78 Hz, 1H), 2.29 (m, 1H), 2.52 (dd, 16.56, 8.53Hz, 1H), 2.77 (t, 6.27 Hz, 2H), 2.97 (dd, 9.54, 6.78 Hz, 1H), 3.35 (m,2H), 3.46 (dd, 9.29, 8.03 Hz, 1H), 4.83 (m, 2H), 6.64 (t, 7.16 Hz, 1H),6.79 (d, 8.29 Hz, 1H), 6.97 (d, 7.28 Hz, 1H), 7.06 (m, 1H) 296 41-(8H-isothiazolo[5,4-b]indol-8- 314 (DMSO): 0.79 (t, 7.15 Hz, 3H),1.12-1.37 (m, ylmethyl)-4-propylpyrrolidin-2-one 4H), 2.01 (m, 1H), 2.23(m, 1H), 2.44 (dd, 16.58, 8.67 Hz, 1H), 2.93 (m, 1H), 3.45 (t, 8.54 Hz,1H), 5.74 (s Hz, 2H), 7.34 (m, 4H), 7.77 (d, 8.04 Hz, 1H), 8.11 (d, 7.53Hz, 1H) 297 1-(1H-1,2,4-triazol-1- (DMSO): 1.94 (m, 2H), 2.28 (t, J 8Hz, 2H), ylmethyl)pyrrolidin-2-one 2.32-2.44 (m, 2H overlapped withsolvent), 1.45 (s, 2H), 8.00 (s, 1H), 8.56 (s, 1H) 298 41-[(2,5-dichloro-1H-pyrrol-1- 275/277/279 (DMSO): 0.83 (t, J 7.3 Hz,3H), 1.24 (m, 4H), yl)methyl]-4-propylpyrrolidin-2-one 1.96 (dd, J 16.6;7.3 Hz, 1H; 2.83 (m, 1H), 2.41 (dd, J 16.6; 8.5 Hz, 1H), 2.75 (dd, J9.3; 6.5 Hz, 1H), 3.29 (m, overlapped with solvent, 1H), 5.38 (s, 2H),6.22 (s, 2H) 299 4 1-[(2-chloro-1H-pyrrol-1-yl)methyl]- 241/243 (DMSO):0.84 (t, J 7.3 Hz, 3H), 1.25 (m, 4H), 4-propylpyrrolidin-2-one 1.96 (dd,J 16.6; 7.3 Hz, 1H; 2.83 (m, 1H), 2.24 (dd, J 16.6; 8.5 Hz, 1H), 2.85(dd, J 9.3; 6.5 Hz, 1H), 3.39 (dd, J 9.3; 7.9 Hz, 1H), 5.27 (d, J 14.5Hz, 1H), 5.34 (d, J 14.05 Hz, 1H), 6.08 (m, 2H), 6.86 (t, J 2.8 hz, 1H)300 4 1-[(2-chloro-1H-benzimidazol-1- 312/314 0.85 (t, 7.02 Hz, 3H),1.28 (m, 4H), yl)methyl]-4-propylpyrrolidin-2-one 2.07 (dd, 16.48, 7.93Hz, 1H), 2.29 (m, 1H), 2.54 (m, 1H), 2.94 (dd, 9.31, 6.87 Hz, 1H), 3.47(m, 1H), 5.67 (s, 2H), 7.30 (m, 2H), 7.66 (m, 2H) 301 41-[(2-chloro-1H-benzimidazol-1- 326 2.59 (dd, 17.18, 8.34 Hz, 1H), 2.85(dd, yl)methyl]-4-phenylpyrrolidin-2-one 17.18, 9.09 Hz, 1H), 3.35 (dd,9.60, 7.20 Hz, 1H), 3.53 (m, 1H), 3.77 (m, 1H), 5.76 (m, 2H), 7.08 (m,2H), 7.24 (m, 3H), 7.33 (m, 2H), 7.69 (m, 2H) 302 42-chloro-1-[(2-oxo-4- 317/319 (DMSO): 0.80 (t, 7 Hz, 3H), 1.28 (m, 4H),propylpyrrolidin-1-yl)methyl]-1H- 2 (m, 1H), 2.25 (m, 1H), 2.44 (m, 1H),benzimidazole-5-carbonitrile 2.99 (m, 1H), 3.51 (m, 1H), 5.74 (s, 2H),7.78 (m, 1H), 7.89 (m, 1H), 8.21 (s, 1H) 303 4 2-chloro-1-[(2-oxo-4-317/319 (DMSO): 0.85 (t, 7.03 Hz, 3H), 1.28 (m, 4H),propylpyrrolidin-1-yl)methyl]-1H- 2.02 (m, 1H), 2.28 (m, 1H), 2.44 (m,1H), benzimidazole-6-carbonitrile 3.02 (m, 1H), 3.51 (m, 1H), 5.72 (s,2H), 7.70 (m, 1H), 7.81 (m, 1H), 8.23 (s, 1H) 304 44-propyl-1-[(2,5,6-trichloro-1H- 360/362/364 0.88 (t, 7.05 Hz, 3H), 1.31(m, 5H), benzimidazol-1-yl)methyl]pyrrolidin- 2.10 (dd, 17.12, 8.18 Hz,1H), 2.34 (m, 1H), 2-one 2.56 (dd, 17.12, 8.56 Hz, 1H), 2.98 (dd, 9.32,7.05 Hz, 1H), 3.50 (m, 1H), 5.62 (m, 2H), 7.76 (s, 1H), 7.84 (s, 1H) 3054 1-[(2-chloro-6-methoxy-1H- 322/324 0.87 (t, 7.15 Hz, 3H), 1.30 (m,4H), benzimidazol-1-yl)methyl]-4- 2.08 (dd, 16.81, 8.16 Hz, 1H), 2.32(m, 1H), propylpyrrolidin-2-one 2.54 (dd, 17.07, 8.66 Hz, 1H), 2.96 (dd,9.29, 7.03 Hz, 1H), 3.48 (m, 1H), 3.85 (s, 3H), 5.63 (s, 2H), 6.90 (dd,8.78, 2.38 Hz, 1H), 7.23 (d, 2.38 Hz, 1H), 7.54 (d, 8.78 Hz, 1H) 306 41-[(2-chloro-5-methoxy-1H- 322/324 0.86 (t, 7.15 Hz, 3H), 1.28 (m, 4H),benzimidazol-1-yl)methyl]-4- 2.07 (dd, 17.07, 7.91 Hz, 1H), 2.30 (m,1H), propylpyrrolidin-2-one 2.53 (dd, 17.07, 8.66 Hz, 1H), 2.93 (dd,9.29, 6.90 Hz, 1H), 3.45 (m, 1H), 3.84 (s, 3H), 5.64 (s, 2H), 6.94 (dd,9.03, 2.38 Hz, 1H), 7.15 (d, 2.26 Hz, 1H), 7.52 (d, 8.78 Hz, 1H) 307 41-[(2-chloro-6-nitro-1H- 337/339 0.88 (t, 7.28 Hz, 3H), 1.33 (m, 4H),benzimidazol-1-yl)methyl]-4- 2.11 (dd, 17.08, 8.04 Hz, 1H), 2.36 (m,1H), propylpyrrolidin-2-one 2.58 (dd, 17.08, 8.79 Hz, 1H), 3.03 (dd,9.29, 7.03 Hz, 1H), 3.55 (m, 1H), 5.76 (m, 2H), 7.76 (d, 8.79 Hz, 1H),8.24 (dd, 9.04, 2.26 Hz, 1H), 8.72 (d, 2.01 Hz, 1H) 308 41-[(2-chloro-5-nitro-1H- 337/339 0.88 (t, 7.15 Hz, 3H), 1.32 (m, 4H),benzimidazol-1-yl)methyl]-4- 2.10 (dd, 17.07, 8.03 Hz, 2H), 2.35 (m,1H), propylpyrrolidin-2-one 2.57 (dd, 17.07, 8.53 Hz, 1H), 3.01 (dd,9.03, 7.03 Hz, 1H), 3.54 (t, 8.66 Hz, 1H), 5.73 (s, 3H), 7.76 (d, 9.03Hz, 1H), 8.25 (dd, 9.03, 1.76 Hz, 1H), 8.59 (d, 1.76 Hz, 1H) 309 41-[(2-chloro-6-methyl-1H- 306/308 0.86 (t, 7.15 Hz, 3H), 1.29 (m, 4H),benzimidazol-1-yl)methyl]-4- 2.09 (dd, 16.81, 8.16 Hz, 2H), 2.31 (m,1H), propylpyrrolidin-2-one 2.48 (s, 3H), 2.56 (m, 1H), 2.94 (dd, 9.29,7.28 Hz, 1H), 3.46 (m, 1H), 5.65 (m, 2H), 7.12 (d, 8.28 Hz, 1H), 7.42(s, 1H), 7.55 (d, 8.03 Hz, 1H) 310 4 1-[(2-chloro-1H-benzimidazol-1-312/314 2.23 (dd, 17.07, 8.41 Hz, 1H), 2.66 (dd, yl)methyl]-4-(2,2-17.07, 8.66 Hz, 1H), 3.12 (m, 2H), 3.58 (m,difluorovinyl)pyrrolidin-2-one 1H), 4.13 (m, 1H), 5.71 (m, 2H), 7.26 (s,1H), 7.32 (m, 2H), 7.64 (m, 1H), 7.69 (m, 1H) 311 41-[(6-bromo-2-chloro-1H- 370/372/374 (DMSO): 0.81 (t, 7.15 Hz, 3H), 1.24(m, 4H), benzimidazol-1-yl)methyl]-4- 2.01 (dd, 16.56, 7.78 Hz, 1H),2.26 (m, 1H), propylpyrrolidin-2-one 2.44 (dd, 16.56, 8.53 Hz, 1H), 2.98(dd, 9.03, 6.78 Hz, 1H), 3.51 (m, 1H), 5.65 (s, 2H), 7.43 (dd, 8.53,1.51 Hz, 1H), 7.58 (m, 1H), 7.96 (d, 1.76 Hz, 1H) 312 41-[(5-bromo-2-chloro-1H- 370/372/374 (DMSO): 0.80 (t, 7.15 Hz, 3H), 1.22(m, 4H), benzimidazol-1-yl)methyl]-4- 1.99 (dd, 16.81, 7.78 Hz, 1H),2.24 (m, 1H), propylpyrrolidin-2-one 2.43 (dd, 16.81, 8.66 Hz, 1H), 2.94(dd, 9.03, 6.78 Hz, 1H), 3.47 (t, 8.53 Hz, 1H), 5.66 (s, 2H), 7.51 (dd,8.53, 1.63 Hz, 1H), 7.66 (m, 1H), 7.85 (d, 1.76 Hz, 1H) 313 41-[(2-chloro-6-fluoro-1H- 310/312 0.87 (m, 3H), 1.31 (m, 4H), 2.09 (dd,16.87, benzimidazol-1-yl)methyl]-4- 7.98 Hz, 1H), 2.32 (m, 1H), 2.46 (m,2H), propylpyrrolidin-2-one 2.97 (dd, 9.35, 6.97 Hz, 1H), 3.49 (m, 1H),5.63 (s, 2H), 7.04 (td, 9.17, 2.38 Hz, 1H), 7.42 (dd, 8.62, 2.38 Hz,1H), 7.60 (dd, 8.99, 4.68 Hz, 1H) 314 4 1-[(2-chloro-5-fluoro-1H-310/312 0.87 (t, 7.15 Hz, 3H), 1.29 (m, 4H), 2.08 (m,benzimidazol-1-yl)methyl]-4- 1H), 2.32 (m, 1H), 2.55 (dd, 17.07, 8.53Hz, propylpyrrolidin-2-one 1H), 2.96 (dd, 9.29, 6.78 Hz, 1H), 3.48 (m,1H), 5.66 (s, 2H), 7.06 (td, 9.29, 2.32 Hz, 1H), 7.36 (dd, 9.03, 2.51Hz, 1H), 7.62 (dd, 9.03, 4.52 Hz, 1H) 315 41-[(2,6-dichloro-1H-benzimidazol-1- 326/328/330 0.87 (m, 3H), 1.29 (m,4H), 2.08 (m, 1H), yl)methyl]-4-propylpyrrolidin-2-one 2.32 (m, 1H),2.54 (dd, 17.06, 8.62 Hz, 1H), 2.95 (dd, 9.35, 6.97 Hz, 1H), 3.48 (m,1H), 5.66 (s, 2H), 7.28 (m, 2H), 7.61 (d, 8.62 Hz, 1H), 7.66 (d, 1.83Hz, 1H) 316 4 1-[(2,5-dichloro-1H-benzimidazol-1- 326/328/330 0.87 (t,7.15 Hz, 3H), 1.32 (m, 4H), 2.09 (m, yl)methyl]-4-propylpyrrolidin-2-one1H), 2.33 (m, 1H), 2.56 (dd, 17.06, 8.62 Hz, 1H), 2.97 (dd, 9.17, 7.15Hz, 1H), 3.49 (m, 1H), 5.64 (s, 2H), 7.27 (m, 1H), 7.58 (d, 8.62 Hz,1H), 7.69 (d, 1.47 Hz, 1H) 317 4 1-{[2-chloro-6-(trifluoromethyl)-1H-360/362 0.87 (t, 7.15 Hz, 3H), 1.31 (m, 4H),benzimidazol-1-yl]methyl}-4- 2.09 (dd, 16.81, 8.16 Hz, 1H), 2.34 (m,1H), propylpyrrolidin-2-one 2.56 (dd, 17.07, 8.53 Hz, 1H), 2.99 (dd,9.29, 7.03 Hz, 1H), 3.51 (m, 1H), 5.72 (s, 2H), 7.56 (d, 8.53 Hz, 1H),7.77 (d, 8.53 Hz, 1H), 8.04 (s Hz, 1H) 318 41-{[2-chloro-5-(trifluoromethyl)-1H- 360/362 0.87 (t, 7.15 Hz, 3H), 1.29(m, 4H), 2.08 (m, benzimidazol-1-yl]methyl}-4- 1H), 2.33 (m, 1H), 2.55(dd, 16.87, 8.53 Hz, propylpyrrolidin-2-one 1H), 2.98 (m, 1H), 3.50 (m,1H), 5.71 (s, 2H), 7.56 (d, 8.62 Hz, 1H), 7.80 (d, 8.62 Hz, 1H), 7.96(s, 1H) 319 1-[(2-chloro-1H-benzimidazol-1- 250/252 2.01 (m, 2H), 2.42(m, 2H), 3.38 (m, 2H), yl)methyl]pyrrolidin-2-one 5.71 (s, 2H), 7.29 (m,2H), 7.67 (m, 2H) 320 4 1-[(2-chloro-6-hydroxy-1H- 308/310 (DMSO): 0.80(t, 7.15 Hz, 3H), 1.23 (m, 4H), benzimidazol-1-yl)methyl]-4- 2.00 (dd,16.81, 7.65 Hz, 1H), 2.24 (m, 1H), propylpyrrolidin-2-one 2.44 (dd,16.56, 8.53 Hz, 1H), 2.91 (dd, 9.03, 6.78 Hz, 1H), 3.43 (m, 1H), 5.54(m, 2H), 6.73 (dd, 8.78, 2.26 Hz, 1H), 7.02 (m, 1H), 7.38 (m, 1H), 9.53(s, OH, 1H) 321 4 1-[(2-chloro-5-hydroxy-1H- 308/310 (DMSO): 0.87 (t,7.28 Hz, 3H), 1.31 (m, 4H), benzimidazol-1-yl)methyl]-4- 2.07 (m, 1H),2.3 (m, 1H), 2.55 (m, 1H), propylpyrrolidin-2-one 3.00 (m, 1H), 3.52 (m,1H), 5.70 (s, 2H), 6.95 (dd, 8.78, 2.01 Hz, 1H), 7 (s, 1H), 7.58 (d,9.03 Hz, 1H), 9.3 (s, OH, 1H)

Example 95 LBS Binding Assay

[LBS stands for Levetiracetam Binding Site cf. M. Noyer et al., Eur. J.Pharmacol. (1995), 286, 137-146.]

The inhibition constant (K_(i)) of a compound is determined incompetitive binding experiments by measuring the binding of a singleconcentration of a radioactive ligand at equilibrium with variousconcentrations of the unlabeled test substance. The concentration of thetest substance inhibiting 50% of the specific binding of the radioligandis called the IC₅₀. The equilibrium dissociation constant K_(i) isproportional to the IC₅₀ and is calculated using the equation of Chengand Prusoff (Cheng Y. et al., Biochem. Pharmacol. (1972), 22,3099-3108).

The concentration range usually encompasses 6 log units with variablesteps (0.3 to 0.5 log). Assays are performed in mono- or duplicate, eachK_(i) determination is performed on two different samples of testsubstance.

Cerebral cortex from 200-250 g male Sprague-Dawley rats are homogenisedusing a Potter S homogeniser (10 strokes at 1,000 rpm; Braun, Germany)in 20 mmol/l Tris-HCl (pH 7.4), 250 mmol/l sucrose (buffer A); alloperations are performed at 4° C. The homogenate is centrifuged at30,000 g for 15 min. The crude membrane pellet obtained is resuspendedin 50 mmol/l Tris-HCl (pH 7.4), (buffer B) and incubated 15 min at 37°C., centrifuged at 30,000 g for 15 min and washed twice with the samebuffer. The final pellet is resuspended in buffer A at a proteinconcentration ranging from 15 to 25 mg/ml and stored in liquid nitrogen.

Membranes (150-200 μg of protein/assay) are incubated at 4° C. for 120min in 0.5 ml of a 50 mmol/l Tris-HCl buffer (pH 7.4) containing 2mmol/l MgCl₂, 1 to 2 10⁻⁹ mol/l of[³H]-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide and increasingconcentrations of the test compound of formula (I). The non specificbinding (NSB) is defined as the residual binding observed in thepresence of a concentration of reference substance (e.g. 10⁻³ mol/llevetiracetam) that binds essentially all the receptors. Membrane-boundand free radioligands are separated by rapid filtration through glassfiber filters (equivalent to Whatman GF/C or GF/B; VEL, Belgium)pre-soaked in 0.1% polyethyleneimine and 10⁻³ mol/l levetiracetam toreduce non specific binding. Samples and filters are rinsed by at least6 ml of 50 mmol/l Tris-HCl (pH 7.4) buffer. The entire filtrationprocedure does not exceed 10 seconds per sample. The radioactivitytrapped onto the filters is counted by liquid scintillation in aβ-counter (Tri-Carb 1900 or TopCount 9206, Camberra Packard, Belgium, orany other equivalent counter). Data analysis is performed by acomputerized non linear curve fitting method using a set of equationsdescribing several binding models assuming populations of independentnon-interacting receptors, which obey the law of mass.

Example 96 Animal Model of Sound-Susceptible Mice

The objective of this test is to evaluate the anticonvulsant potency ofa compound in sound-susceptible mice, a genetic animal model with reflexseizures. In this model of primary generalised epilepsy, seizures areevoked without electrical or chemical stimulation and the seizure typesare, at least in part, similar in their clinical phenomenology toseizures occurring in man (Löscher W. & Schmidt D., Epilepsy Res.(1998), 2, 145-181; Buchhalter J. R., Epilepsia (1993), 34, S31-S41).

Male or female genetically sound-sensitive mice (14-28 g; N=10), derivedfrom a DBA strain originally selected by Dr. Lehmann of the Laboratoryof Acoustic Physiology (Paris) and bred in the UCB Pharma Sectorhusbandry unit since 1978, are used. The experimental design consistedof several groups, one group receiving the vehicle control and the othergroups different doses of the test-compound. The compounds areadministered intraperitoneally 60 minutes before the induction ofaudiogenic seizures. The range of the doses administered had alogarithmic progression, generally between 1.0×10⁻⁵ mol/kg and 1.0×10⁻³mol/kg, but lower or higher doses are tested if necessary.

For testing, the animals are placed in small cages, one mouse per cage,in a sound-attenuated chamber. After a period of orientation of 30seconds, the acoustic stimulus (90 dB, 10-20 kHz) is delivered for 30seconds via loudspeakers positioned above each cage. During thisinterval, the mice are observed and the presence of the 3 phases of theseizure activity namely wild running, clonic and tonic convulsions, isrecorded. The proportion of mice protected against wild running, clonicand tonic convulsions, respectively, is calculated.

For active compounds, an ED₅₀ value, i.e. the dose producing 50%protection relative to the control group, together with 95% confidencelimits, is calculated using a Probit Analysis (SAS/STAT® Software,version 6.09, PROBIT procedure) of the proportions of protected mice foreach of the 3 phases of the seizure activity.

Compounds synthesized according to the procedure described in examples 1to 94 and described in table 1 (except compounds 106, 180, 222 and 225)are tested in the SV2 binding assay and/or audiogenic seizure in mice,according to the procedure described above, and are found active.

1. A compound having the structural formula I

or a geometric isomer, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen, C₁₋₁₂ alkyl, aryl or heterocycle; R² is hydrogen; or R¹ and R² are linked together to form a C₃₋₆ cycloalkyl; R³ is a) an unsubstituted or substituted heterocycle linked to the rest of the molecule via one of its C atoms; or b) an unsubstituted or substituted heterocycle linked to the rest of the molecule via one of its N atoms selected from the group consisting of 1H-1,2,3-benzotriazol-1-yl; 1H-imidazo[4,5-b]pyridin-1-yl; 3H-imidazo[4,5-b]pyridin-3-yl; 7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl; 2,3-dihydro-1H-indol-lyl; 9H-purin-9-yl; 1H-pyrazolo[3,4-b]pyridin-1-yl; 2H-pyrazolo[3,4-b]pyridin-2-yl; 1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl; 3,4-dihydroquinolin-1(2H)-yl; 8H-isothiazolo[5,4-b]indol-8-yl; 1H-1,2,4-triazol-1-yl; 1H-1,2,3-triazol-1-yl; 1H-pyrrol-1-yl; 1H-tetrazol-1-yl; and 2-chloro-1H-benzimidazol-1-yl; R⁴ is hydrogen; C₁₋₁₂ alkyl optionally substituted by halogen, C₁₋₄ alkoxy, C₁₋₄ alkylthio, azido, nitrooxy or aryl; C₂₋₁₂ alkenyl; C₂₋₁₂ alkynyl; aryl non-substituted by a cycloalkoxy; azido; alkoxy-carbonylamino; arylsulfonyloxy; or heterocycle; R⁵ is hydrogen; or R⁴ together with R⁵ forms an optionally substituted benzene ring such that the compound of structural formula (I) has the structure:

wherein R⁶ is hydrogen or halogen; R⁷ is hydrogen; nitro; halogen; heterocycle; amino; aryl; C₁₋₁₂ alkyl optionally substituted by at least one halogen; or C₁₋₁₂ alkoxy optionally substituted by at least one halogen; R⁸ is hydrogen, C₁₋₁₂ alkyl or halogen; and R⁹ is hydrogen, C₁₋₁₂ alkyl or halogen; with the provisos that R⁴ is not hydrogen when R¹, R² and R⁵ are hydrogen, and R³ is substituted or unsubstituted 3-pyridinyl; unsubstituted 4-pyridinyl; 2-(phenylamino)pyrimidin-4-yl; 2-trifluoropyrimidin-4-yl; isoxazol-5-yl 3-substituted by an aryl or an heterocycle; a substituted 1H-pyrazol-5-yl; a substituted 1H-pyrazol-3-yl; a 3-substituted 1,2,4-oxadiazol-5-yl; an unsubstituted or 1-substituted 1H-indol-3-yl; 2-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]thiazol-5-yl; (2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl); 5-(4-methoxyphenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl; substituted or unsubstituted 1,2,4-triazol-3-yl; substituted or unsubstituted 1,2,4-triazol-5-yl; 4,5,6,7-tetrahydro-2,1-benzisoxazol-3-yl; substituted 4,5-dihydroisoxazol-5-yl; substituted or unsubstituted 1H-1,2,3-benzotriazol-3-yl; 5-substituted 1,2,4-oxadiazol-3-yl; unsubstituted 1H-imidazo[4,5-c]pyridin-2-yl; 1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-purin-9-yl; substituted or unsubstituted 2-thienyl; substituted or unsubstituted 2-furyl; substituted or unsubstituted 2-pyrrolyl; substituted to unsubstituted 2-benzimidazol-2-yl; or 1-substituted 1H-indol-2-yl; R⁴ is not phenyl when R¹, R² and R⁵ are hydrogen, and R³ is a substituted 1,2,4-triazol-3-yl; a substituted 1,2,4-triazol-5-yl; or unsubstituted 1H-benzimidazol-2-yl; R⁴ is not hydrogen or phenyl when R¹ is hydrogen or C1′-2 alkyl, R² and R⁵ are hydrogen, and R³ is a substituted or unsubstituted non aromatic heterocycle; R⁴ is not hydrogen when R¹ is C1′-2 alkyl, R² and R⁵ are hydrogen, and R³ is a 3-substituted 1,2,4-oxadiazol-5-yl or unsubstituted 3-indolyl; R⁴ is not hydrogen when R¹ is phenyl, C₁₋₁₂ alkyl or heterocycle, R² and R⁵ are hydrogen, and R³ is unsubstituted 1,2,3-benzotriazol-1-yl or unsubstituted 1,2,4-triazol-1-yl; R¹ is not 1-pyrrolidin-2-one when R², R⁴ and R⁵ are hydrogen, and R³ is 2-furyl; and R¹ is not 4-(2-pyrimidinyl)-1-piperazinyl when R², R⁴ and R⁵ are hydrogen, and R³ is 1-methyl-1H-pyrrol-2-yl.
 2. The compound according to claim 1, wherein R³ is a unsubstituted or substituted unsaturated heterocycle comprising at least one sp² hybridized nitrogen in the beta-, gamma- or delta-position of the carbon attached to the methylpyrrolidinone moiety; or a unsubstituted or substituted heterocycle selected from the group consisting of 1H-1,2,3-benzotriazol-1-yl; 1H-imidazo[4,5-b]pyridin-1-yl; 3H-imidazo[4,5-b]pyridin-3-yl; 7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl; 2,3-dihydro-1H-indol-lyl; 9H-purin-9-yl; 1H-pyrazolo[3,4-b]pyridin-1-yl; 2H-pyrazolo[3,4-b]pyridin-2-yl; 1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl; 3,4-dihydroquinolin-1(2H)-yl; 8H-isothiazolo[5,4-b]indol-8-yl; 1H-1,2,4-triazol-1-yl; 1H-1,2,3-triazol-1-yl; 1H-pyrrol-1-yl; and 1H-tetrazol-1-yl.
 3. A The compound according to claim 1, wherein R³ is a unsubstituted or substituted aromatic heterocycle comprising at least one sp² hybridized nitrogen in the beta-, gamma- or delta-position of the carbon attached to the methylpyrrolidinone moiety; or a unsubstituted or substituted heterocycle selected from the group consisting of 1H-1,2,3-benzotriazol-1-yl; 1H-imidazo[4,5-b]pyridin-1-yl; 3H-imidazo[4,5-b]pyridin-3-yl; 7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl; 2,3-dihydro-1H-indol-lyl; 9H-purin-9-yl; 1H-pyrazolo[3,4-b]pyridin-1-yl; 2H-pyrazolo[3,4-b]pyridin-2-yl; 1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl; 3,4-dihydroquinolin-1(2H)-yl; 8H-isothiazolo[5,4-b]indol-8-yl; 1H-1,2,4-triazol-1-yl; and 1H-pyrrol-1-yl.
 4. The compound according to claim 1,

wherein R¹ is hydrogen; R² is hydrogen; R³ is (a) a heterocycle selected from the group consisting of: 1H-benzimidazol-6-yl; 1H-benzimidazol-7-yl; imidazo[1,2-a]pyridin-3-yl; imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b][1,2,4]triazin-7-yl; imidazo[1,2-b]pyridazin-3-yl; 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl; imidazo[2,1-b][1,3]thiazol-5-yl; 3H-imidazo[4,5-b]pyridin-7-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; 1H-indol-2-yl; 1H-indol-3-yl; 1H-indol-4-yl; 1H-indol-7-yl; isoxazol-4-yl; 1H-pyrazol-4-yl; 1H-pyrazol-5-yl; 1H-pyrazolo[1,5-a]pyrimidin-3-yl; 1H-pyrazolo[3,4-b]pyridin-3-yl; pyridazin-4-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; 1H-pyrrolo[2,3-b]pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-4-yl; 1H-pyrrolo[2,3-b]pyridin-5-yl; 1H-pyrrolo[2,3-c]pyridin-2-yl; 1H-pyrrolo[2,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; 1H-pyrrolo[3,2-c]pyridin-2-yl; 1H-pyrrolo[3,2-c]pyridin-3-yl; 1,3,4-thiadiazol-2-yl; 1,3-thiazol-5-yl; [1,2,4]triazolo[4,3-b]pyridazin-7-yl; [1,2,4]triazolo[4,3-b]pyridazin-8-yl; and indolizin-3-yl; or (b) a heterocycle selected from the group consisting of: 1H-1,2,3-benzotriazol-1-yl; 1H-imidazo[4,5-b]pyridin-1-yl; 3H-imidazo[4,5-b]pyridin-3-yl; 7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl; 2,3-dihydro-1H-indol-lyl; 9H-purin-9-yl; 1H-pyrazolo[3,4-b]pyridin-1-yl; 2H-pyrazolo[3,4-b]pyridin-2-yl; 1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl; 3,4-dihydroquinolin-1(2H)-yl; 8H-isothiazolo[5,4-b]indol-8-yl; 1H-1,2,4-triazol-1-yl; and 1H-pyrrol-1-yl; R⁴ is C₁₋₁₂ alkyl optionally substituted by halogen or C₁₋₄ alkoxy; C₂₋₁₂ alkenyl; or C₂₋₁₂ alkynyl; R⁵ is hydrogen; or R⁴ together with R⁵ forms an optionally substituted benzene ring such that the compound of structural formula (I) has the structure:

wherein R⁶ is hydrogen or halogen; R⁷ is hydrogen; nitro; halogen; heterocycle; amino; aryl; C₁₋₁₂ alkyl; or C₁₋₁₂ alkoxy; R⁸ is hydrogen, C₁₋₁₂ alkyl or halogen; and R⁹ is hydrogen, C₁₋₁₂ alkyl or halogen.
 5. The compound according to claim 4, wherein R⁴ is n-propyl; 2,2,2-trifluoroethyl; 2-chloro-2,2-difluoroethyl; 2-bromo-2,2-difluoroethyl; or 2,2-difluorovinyl.
 6. The compound according to claim 4, wherein R⁴ together with R⁵ forms an optionally substituted benzene ring such that the compound of structural formula (I) has the structure:

wherein R⁶ is hydrogen; R⁷ is chlorine; R⁸ is hydrogen; and R⁹ is hydrogen.
 7. The compound according to claim 4, wherein R³ is a heterocycle selected from the group consisting of: imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b][1,2,4]triazin-7-yl; imidazo[1,2-b]pyridazin-3-yl; 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl; imidazo[2,1-b][1,3]thiazol-5-yl; 3H-imidazo[4,5-b]pyridin-7-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; isoxazol-4-yl; 1H-pyrazol-4-yl; 1H-pyrazol-5-yl; 1H-pyrazolo[1,5-a]pyrimidin-3-yl; 1H-pyrazolo[3,4-b]pyridin-3-yl; pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-4-yl; 1H-pyrrolo[2,3-b]pyridin-5-yl; 1H-pyrrolo[2,3-c]pyridin-2-yl; 1H-pyrrolo[2,3-c]pyridin-3-yl; 1,3-thiazol-5-yl; [1,2,4]triazolo[4,3-b]pyridazin-8-yl; and indolizin-3-yl.
 8. The compound according to claim 4, wherein R³ is imidazo[1,2-a]pyridin-3-yl.
 9. The compound according to claim 4, wherein R³ is a heterocycle selected from the group consisting of: 3H-imidazo[4,5-b]pyridin-3-yl; 1H-indol-1-yl; 1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl; and 1H-pyrrol-1-yl.
 10. The compound according to claim 4, wherein R¹, R² and R⁵ are hydrogen; R⁴ is C₁₋₆ alkyl optionally substituted by halogen; C₂₋₆ alkenyl optionally substituted by halogen; or C₂₋₁₂ alkynyl optionally substituted by halogen; and R³ is a heterocycle selected from the group consisting of: imidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl; imidazo[2,1-b][1,3]thiazol-5-yl; 3H-imidazo[4,5-b]pyridin-7-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; 1H-pyrazol-4-yl; 1H-pyrazolo[1,5-a]pyrimidin-3-yl; pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-4-yl; and 1,3-thiazol-5-yl.
 11. The compound according to claim 4, wherein R¹, R² and R⁵ are hydrogen; R⁴ is C₁₋₆ alkyl optionally substituted by halogen; C₂₋₆ alkenyl optionally substituted by halogen; or C₂₋₁₂ alkynyl optionally substituted by halogen; and R³ is a heterocycle selected from the group consisting of: 3H-imidazo[4,5-b]pyridin-3-yl; 3H-imidazo[4,5-b]pyridin-1-yl; and 1H pyrrolo[2,3-b]pyridin-1-yl.
 12. The compound according to claim 1, selected from the group consisting of: 1-[(1-methyl-1H-benzimidazol-6-yl)methyl]-4-propylpyrrolidin-2-one; 1-(1H-benzimidazol-7-ylmethyl)-4-propylpyrrolidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one; 1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-phenylpyrrolidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one; 1-[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(8-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-iodoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(7-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6,8-dibromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6,8-dichloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(6-chloro-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-propylpyrrolidin-2-one; 1-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-phenylpyrrolidin-2-one; 1-[(6-chloroimidazo[1,2-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-phenylimidazo[1,2-b][1,2,4]triazin-7-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-phenylpyrrolidin-2-one; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-phenylpyrrolidin-2-one; 5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one; 1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-(benzyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-(dimethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2-chloro-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 1-{[6-(methylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 4-(2-bromo-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 1-{[6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one; 1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-(ethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-propyl-1-{[6-pyrrolidin-1-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2-bromo-2,2-difluoroethyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 1-{[6-(cyclopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-(isopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-({2-cyclopropyl-6-[(2-fluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-({2-cyclopropyl-6-[(2,2-difluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-({2-cyclopropyl-6-[(2,2,2-trifluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one; 4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 1-{[2-cyclopropyl-6-(cyclopropylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(3-chloro-4-fluorophenyl)pyrrolidin-2-one; 1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-{[6-(cyclobutylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(2-cyclopropyl-6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-ethoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 1-{[6-(cyclopropylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-{[6-(cyclobutylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-{[6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carbonitrile; 4-(2,2-difluorovinyl)-1-{[6-thien-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-{[6-pyridin-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 4-propyl-1-{[2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one; 1-[(6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-methylimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one; 1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-phenylpyrrolidin-2-one; 4-phenyl-1-[(5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]pyrrolidin-2-one; 4-phenyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one; 1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one; 1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-phenyl-3H-imidazo[4,1-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one; 1-[1-(1H-imidazol-4-yl)methyl]pyrrolidin-2-one; 1-[(5-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one; 1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one; 1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-4-yl}methyl)-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-bromo-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-bromo-1H-imidazol-4-yl)methyl]-5-chloro-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-5-ylmethyl)pyrrolidin-2-one; 1-[(1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one; 1-methyl-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile; 1-(1H-imidazol-5-ylmethyl)-4-phenylpyrrolidin-2-one; 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one; 1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one; 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile; 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide; N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide; 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile; 1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one; benzyl 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-2-ylcarbamate; 1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one; 5-chloro-1-(1H-imidazol-5-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-[(2,4-dichloro-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 5-chloro-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-2H-indol-2-one; 1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-indol-2-ylmethyl)-4-propylpyrrolidin-2-one; 1-(1H-indol-3-ylmethyl)-4-propylpyrrolidin-2-one; 3-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-5-carbonitrile; 1-[(2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(7-methoxy-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-{[6-(trifluoromethyl)-1H-indol-3-yl]methyl}pyrrolidin-2-one; 1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(7-fluoro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[1H-indol-3-yl(phenyl)methyl]-4-propylpyrrolidin-2-one; 1-[1-(1H-indol-3-yl)propyl]-4-propylpyrrolidin-2-one; 1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one; 3-[(2-oxo-4-propylpyrrolidin-1-yl)(phenyl)methyl]-1H-indole-5-carbonitrile; 1-(1H-indol-4-ylmethyl)-4-propylpyrrolidin-2-one; 1-(1H-indol-7-ylmethyl)-4-propylpyrrolidin-2-one; 1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one; 1-[(1-phenyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 4-(2,3,5-trifluorophenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]pyrrolidin-2-one; 4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one; 1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(1-chloro-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(3-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one; (−)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; (+)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-1,3-dihydro-2H-indol-2-one; 1-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(5-amino-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-pyrazol-5-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one; 1-[(6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-6-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-methyl-6-(1H-pyrrol-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-({6-[(1E)-hex-1-enyl]-2-methylpyrazolo[1,5-a]pyrimidin-3-yl}methyl)-4-propylpyrrolidin-2-one; 1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(6-hydroxy-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one; 1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-[(5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one; 1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-{[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one; 1-{[2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-{[6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(5-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 4-propyl-1-(pyridin-3-ylmethyl)pyrrolidin-2-one; (−)-1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one; 5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one; 1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one; 1-[(2-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyrrolidin-2-one; 1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)pyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)pyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)pyrrolidin-2-one; 4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one; 1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one; 1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one; 1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-pyrrolidin-1-yl-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1,3-thiazol-2(3H)-one; 4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one; 4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)methyl]pyrrolidin-2-one; 4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one; 4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one; 4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one; 1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one; 1-{[6-chloro-3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}-4-phenylpyrrolidin-2-one; 1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one; 1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one; 1-[(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(3-chloro-7H-imidazo[4,5-c]pyridazin-7-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-fluoro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-(2,3-dihydro-1H-indol-1-ylmethyl)-4-propylpyrrolidin-2-one; 1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-2-carbonitrile; 1-[(2-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,5-dichloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-(9H-purin-9-ylmethyl)pyrrolidin-2-one; 1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-(benzylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[6-(propylamino)-9H-purin-9-yl]methyl}pyrrolidin-2-one; 1-({6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}methyl)-4-propylpyrrolidin-2-one; 4-propyl-1-[(6-pyrrolidin-1-yl-9H-purin-9-yl)methyl]pyrrolidin-2-one; 1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)pyrrolidin-2-one; 1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one; 1-(8H-isothiazolo[5,4-b]indol-8-ylmethyl)-4-propylpyrrolidin-2-one; 1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one; 1-[(2,5-dichloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-6-carbonitrile; 4-propyl-1-[(2,5,6-trichloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one; 1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-6-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-5-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-6-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-[(6-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-6-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,6-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,5-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one; 1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; and 1-[(2-chloro-5-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one.
 13. A method of treating a disease mediated by the SV2 protein comprising administering to a mammal in need thereof an effective amount of a compound according to claim
 1. 14. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent or carrier.
 15. A method of treatment or prevention of a condition comprising administering to a mammal in need thereof an effective amount of a compound having the structural formula (I)

or a geometric isomer, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen, C₁₋₁₂ alkyl, aryl or 3-8 membered heterocycle; R² is hydrogen; or R¹ and R² may be linked together in such a way to form a C₃₋₆ cycloalkyl; R³ is (a) a heterocycle selected from the group consisting of: 1H-benzimidazol-6-yl; 1H-benzimidazol-7-yl; imidazo[1,2-a]pyridin-3-yl; imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b][1,2,4]triazin-7-yl; imidazo[1,2-b]pyridazin-3-yl; 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl; imidazo[2,1-b][1,3]thiazol-5-yl; 3H-imidazo[4,5-b]pyridin-7-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; 1H-indol-2-yl; 1H-indol-3-yl; 1H-indol-4-yl; 1H-indol-7-yl; isoxazol-4-yl; 1H-pyrazol-4-yl; 1H-pyrazol-5-yl; 1H-pyrazolo[1,5-a]pyrimidin-3-yl; 1H-pyrazolo[3,4-b]pyridin-3-yl; pyridazin-4-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; 1H-pyrrolo[2,3-b]pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-4-yl; 1H-pyrrolo[2,3-b]pyridin-5-yl; 1H-pyrrolo[2,3-c]pyridin-2-yl; 1H-pyrrolo[2,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; 1H-pyrrolo[3,2-c]pyridin-2-yl; 1H-pyrrolo[3,2-c]pyridin-3-yl; 1,3,4-thiadiazol-2-yl; 1,3-thiazol-5-yl; [1,2,4]triazolo[4,3-b]pyridazin-7-yl; [1,2,4]triazolo[4,3-b]pyridazin-8-yl; and indolizin-3-yl; or (b) a heterocycle linked to the rest of the molecule via one of its N atoms selected from the group consisting of: 1H-1,2,3-benzotriazol-1-yl; 1H-imidazo[4,5-b]pyridin-1-yl; 3H-imidazo[4,5-b]pyridin-3-yl; 7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl; 2,3-dihydro-1H-indol-lyl; 9H-purin-9-yl; 1H-pyrazolo[3,4-b]pyridin-1-yl; 2H-pyrazolo[3,4-b]pyridin-2-yl; 1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl; 3,4-dihydroquinolin-1(2H)-yl; 8H-isothiazolo[5,4-b]indol-8-yl; 1H-1,2,4-triazol-1-yl; 1H-pyrrol-1-yl; and 2-chloro-1H-benzimidazol-1-yl; R⁴ is hydrogen; C₁₋₁₂ alkyl optionally substituted by halogen, C₁₋₄ alkoxy, C₁₋₄ alkylthio, azido, nitrooxy; C₂₋₁₂ alkenyl; C₂₋₁₂ alkynyl; or alkoxycarbonylamino; R⁵ is hydrogen; or R⁴ together with R⁵ forms an optionally substituted benzene ring such that the compound of structural formula (I) has the structure:

wherein R⁶ is hydrogen or halogen; R⁷ is hydrogen; nitro; halogen; heterocycle; amino; aryl; C₁₋₁₂ alkyl optionally substituted by at least one halogen; or C₁₋₁₂ alkoxy optionally substituted by at least one halogen; R⁸ is hydrogen, C₁₋₁₂ alkyl or halogen; and R⁹ is hydrogen, C₁₋₁₂ alkyl or halogen; wherein the condition is selected from the group consisting of epilepsy, epileptogenesis, seizure disorders, convulsions, Parkinson's disease, dyskinesia induced by dopamine replacement therapy, tardive dyskinesia induced by administration of neuroleptic drugs, Huntington Chorea, and other neurological disorders including bipolar disorders, mania, depression, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, tremor, essential tremor, simple or complex tics, Tourette syndrome, restless leg syndrome and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity and degenerative diseases, bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis.
 16. The method according to claim 15, wherein, R¹ and R² are both hydrogen; R³ is (a) a heterocycle selected from the group consisting of: imidazo[1,2-a]pyridin-3-yl; imidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl; imidazo[2,1-b][1,3]thiazol-5-yl; 3H-imidazo[4,5-b]pyridin-7-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; 1H-pyrazol-4-yl; 1H-pyrazolo[1,5-a]pyrimidin-3-yl; pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-4-yl; and 1,3-thiazol-5-yl; or (b) a heterocycle selected from the group consisting of: 3H-imidazo[4,5-b]pyridin-3-yl; 1H-indol-1-yl; 1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl; and 1H-pyrrol-1-yl; R⁴ is hydrogen; C₁₋₁₂ alkyl optionally substituted by halogen or C₁₋₄ alkoxy; C₂₋₁₂ alkenyl; or C₂₋₁₂ alkynyl; and R⁵ is hydrogen.
 17. The method according to claim 15, wherein the condition is selected from the group consisting of epilepsy, dyskinesia induced by dopamine replacement therapy, chronic pain, and neuropathic pain.
 18. A compound selected from the group consisting of: methyl 3-(aminomethyl)hexanoate hydrochloride; 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine; 6-bromo-2-(2-thienyl)pyrazolo[1,5-a]pyrimidine; 6-bromo-2-phenylpyrazolo[1,5-a]pyrimidine; 6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidine; 6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidine; 6-chloro-2-phenylpyrazolo[1,5-a]pyrimidine; 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde; 2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde; 6-bromo-2-(2-thienyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde; 6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde; 2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde; 6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde; 5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde; 2-(2-thienyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde; 6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde; ethyl 3-(aminomethyl)hexanoate hydrochloride; 6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine; 3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine; 4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-one; 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide; 4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one; 4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one; 1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one; 4-(2,3,5-trifluorophenyl)-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one; 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; ethyl {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetate; {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetic acid; 4-iodo-3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole; 3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde; 3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde; 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde; 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-5-carbaldehyde; ethyl 4-amino-3-(2,3,5-trifluorophenyl)butanoate hydrochloride; 1-({3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-({3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; ethyl 4-[(pyridazin-4-ylmethylene)amino]butanoate; ethyl 4-[(pyridazin-4-ylmethyl)amino]butanoate; 5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1H-indole; 3,3-dibromo-5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one; 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one; 1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one; 5-bromo-1H-pyrazolo[3,4-b]pyridine; 2-chloro-3-(2-oxopyrrolidin-1-yl)propanal; S-ethyl 4-cyano-1-methyl-1H-imidazole-5-carbothioate; 5-formyl-1-methyl-1H-imidazole-4-carbonitrile; 1-(1H-imidazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; ethyl 4-{[1-(1-trityl-1H-imidazol-4-yl)propyl]amino}butanoate; ethyl 3-{[(2-methyl-1-trityl-1H-imidazol-5-yl)methyl]amino}propanoate; ethyl 3-{[(4-methyl-1-trityl-1H-imidazol-5-yl)methyl]amino}propanoate; 1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine; barium bis[(2-amino-5-chlorophenyl)acetate]; 5-hydroxy-4-(2,2,2-trifluoroethyl)furan-2(5H)-one; 1-benzyl-5-hydroxy-4-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-pyrrol-2-one; 1-benzyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one; 4-(2,2,2-trifluoroethyl)pyrrolidin-2-one; 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine; 6-chloro-2-cyclobutylimidazo[1,2-b]pyridazine; 2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridine; 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde; 6-chloro-2-cyclobutylimidazo[1,2-b]pyridazine-3-carbaldehyde; 2-cyclopropyl-6-fluoroimidazo[1,2-b]pyridazine-3-carbaldehyde; 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde; (6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol; [6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methanol; (6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methanol; (2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methanol; (2-cyclopropyl-6-chloroimidazo[1,2-a]pyridin-3-yl)methanol; 6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine; 2-(2-thienyl)pyrazolo[1,5-a]pyrimidine; 2-(2-furyl)pyrazolo[1,5-a]pyrimidine; 2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidine; 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine; 2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidine; 2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine; 6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine; 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol; 2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-ol; 7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine; 7-chloro-5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine; 7-chloro-2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidine; 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine; 5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine; 2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidine; 4-(2,2-difluorovinyl)-1-(hydroxymethyl)pyrrolidin-2-one; (6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol; (5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol; [2-(2-thienyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol; 3-(chloromethyl)-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine; 3-(chloromethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine; 3-(chloromethyl)-2-(2-thienyl)pyrazolo[1,5-a]pyrimidine; 1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one; 5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridine; 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine; tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate; tert-butyl 5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate; 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; 2,5-dichloro-1H-indole; 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one; 6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine; (5-chloro-2-imino-1,3-thiazol-3(2H)-yl)acetic acid hydrobromide; methyl 3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate; methyl 1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate; methyl 3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-7-carboxylate; 1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxylate; [3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol; [3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol; 7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine; 7-(chloromethyl)-3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine; 1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-phenylpyrrolidin-2-one; 1-{[3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; N-(4-methoxybenzyl)-2-nitroethylene-1,1-diamine; ethyl 2-[(4-methoxybenzyl)amino]-3-nitro-6-(trifluoromethyl)isonicotinate; ethyl 2-[(4-methoxybenzyl)amino]-3-nitro-6-phenylisonicotinate; ethyl 2-[(4-methoxybenzyl)amino]-6-methyl-3-nitroisonicotinate; ethyl 3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate; ethyl 3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridine-7-carboxylate; ethyl 3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridine-7-carboxylate; [3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol; [3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol; [3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol; 7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine; 7-(chloromethyl)-3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridine; 7-(chloromethyl)-3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridine; 1-{[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[3-(4-methoxybenzyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[3-(4-methoxybenzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; methyl 6-bromo-1H-imidazo[4,5-b]pyridine-7-carboxylate; methyl 6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate; [6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol; 6-bromo-7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine; 1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; [3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol; 7-(chloromethyl)-3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridine; 1-{[3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; [3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol; 7-(chloromethyl)-3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridine; 1-{[3-(4-methoxybenzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; 3-(4-methoxybenzyl)-7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine; 2-[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]-N,N-dimethylethylenamine; 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde; 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one; 6-chloro-8-methyl-3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazine; 6-chloro-7-methyl-3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazine; 8-methyl-3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazine; 7-methyl-3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazine; N,N-dimethyl-2-[3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazin-7-yl]ethylenamine; N,N-dimethyl-2-(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)ethylenamine; 3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde; 3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde; N,N-dimethyl-2-[3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazin-8-yl]ethylenamine; 2-[6-chloro-3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazin-8-yl]-N,N-dimethylethylenamine; 3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde; N,N-dimethyl-2-(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)ethylenamine; 2-(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-N,N-dimethylethylenamine; 2-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-N,N-dimethylethylenamine; 3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde; methyl 3-phenyl[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate; 6-chloro[1,2,4]triazolo[4,3-b]pyridazine-8-carbaldehyde; methyl 6-chloro[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate; (6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)(methoxy)methanol; [6-chloro-3-(trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazin-8-yl] (methoxy)methanol; 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde; 4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one; 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde; 4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methyl}pyrrolidin-2-one; 1-(2-fluoroindolizin-3-yl)methanamine; 4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one; 1-{[6-[(2,4-dimethoxybenzyl)amino]-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one; 2-cyclopropyl-7-hydroxypyrazolo[1,5-a]pyrimidin-5(4H)-one; 5,7-dichloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine; 5,7-dichloro-2-cyclopropyl-6-methylpyrazolo[1,5-a]pyrimidine; 5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine; 5-chloro-2-cyclopropyl-6-methylpyrazolo[1,5-a]pyrimidine; 1-(chloromethyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one; 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylic acid; ethyl 3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoate; ethyl 2-formyl-3-(2-oxo-4-propylpyrrolidin-1-yl)propanoate; and 2-benzyl-4-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2,4-dihydro-3H-pyrazol-3-one. 